N-hydroxy 4-sulfonyl butanamide compounds

ABSTRACT

An N-hydroxy sulfonyl butanamide compound that inter alia inhibits matrix metalloprotease activity is disclosed as are a treatment process that comprises administering a contemplated N-hydroxy sulfonyl butanamide compound in a MMP enzyme-inhibiting effective amount to a host having a condition associated with pathological matrix metalloprotease activity.

This application is a 317 of PCT/US 98/04297, filed Mar. 4, 1997 andclaims priority from provisional application No. 60/035,182, filed Mar.4, 1997.

TECHNICAL FIELD

This invention is directed to proteinase (protease) inhibitors, and moreparticularly to N-hydroxy sulfonyl butanamide (hydroxamic acid)compounds that, inter alia, inhibit the activity of matrixmetalloproteinases, compositions of those inhibitors, intermediates forthe syntheses of those compounds, processes for the preparation of thecompounds and processes for treating pathological conditions associatedwith pathological matrix metalloproteinase activity.

BACKGROUND OF THE INVENTION

Connective tissue, extracellular matrix constituents and basementmembranes are required components of all mammals. These components arethe biological materials that provide rigidity, differentiation,attachments and, in some cases, elasticity to biological systemsincluding human beings and other mammals. Connective tissues componentsinclude, for example, collagen, elastin, proteoglycans, fibronectin andlaminin. These biochemicals make up, or are components of structures,such as skin, bone, teeth, tendon, cartilage, basement membrane, bloodvessels, cornea and vitreous humor.

Under normal conditions, connective tissue turnover and/or repairprocesses are controlled and in equilibrium. The loss of this balancefor whatever reason is involved in a number of disease states.Inhibition of the enzymes responsible for a loss of equilibrium providesa control mechanism for this tissue decomposition and, therefore, atreatment for these diseases.

Degradation of connective tissue or connective tissue components iscarried out by the action of proteinase enzymes released from residenttissue cells and/or invading inflammatory or tumor cells. A major classof enzymes involved in this function are the zinc metalloproteinases(metalloproteases, or MMPs).

The metalloprotease enzymes are divided into classes with some membershaving several different names in common use. Examples are: collagenaseI (MMP-1, fibroblast collagenase; EC 3.4.24.3); collagenase II (MMP-8,neutrophil collagenase; EC 3.4.24.34), collagenase III (MMP-13),stromelysin 1 (MMP-3; EC 3.4.24.17), stromelysin 2 (MMP-10; EC3.4.24.22), proteoglycanase, matrilysin (MMP-7), gelatinase A (MMP-2, 72kDa gelatinase, basement membrane collagenase; EC 3.4.24.24), gelatinaseB (MMP-9, 92 kDa gelatinase; EC 3.4.24.35), stromelysin 3 (MMP-11),metalloelastase (MMP-12, HME, human macrophage elastase) and membraneMMP (MMP-14). MMP is an abbreviation or acronym representing the termMatrix Metalloprotease with the attached numerals providingdifferentiation between specific members of the MMP group.

The uncontrolled breakdown of connective tissue by metalloproteases is afeature of many pathological conditions. Examples include rheumatoidarthritis, osteoarthritis, septic arthritis; corneal, epidermal orgastric ulceration; tumor metastasis, invasion or angiogenesis;periodontal disease; proteinuria; Alzheimer's Disease; multiplesclerosis; coronary thrombosis and bone disease. Defective injury repairprocesses can also occur. This can produce improper wound healingleading to weak repairs, adhesions and scarring. These latter defectscan lead to disfigurement and/or permanent disabilities as withpost-surgical adhesions.

Matrix metalloproteases are also involved in the biosynthesis of tumornecrosis factor (TNF) and inhibition of the production or action of TNFand related compounds is an important clinical disease treatmentmechanism. TNF-α, for example, is a cytokine that at present is thoughtto be produced initially as a 28 kD cell-associated molecule. It isreleased as an active, 17 kD form that can mediate a large number ofdeleterious effects in vitro and in vivo. For example, TNF can causeand/or contribute to the effects of inflammation, rheumatoid arthritis,autoimmune disease, multiple sclerosis, graft rejection, fibroticdisease, cancer, infectious diseases, malaria, mycobacterial infection,meningitis, fever, psoriasis, cardiovascular/pulmonary effects such aspost-ischemic reperfusion injury, congestive heart failure, hemorrhage,coagulation, hyperoxic alveolar injury, radiation damage and acute phaseresponses like those seen with infections and sepsis and during shocksuch as septic shock and hemodynamic shock. Chronic release of activeTNF can cause cachexia and anorexia. TNF can be lethal.

TNF-α convertase is a metalloproteinase involved in the formation ofactive TNF-U. Inhibition of TNF-α convertase inhibits production ofactive TNF-α. Compounds that inhibit both MMPs activity have beendisclosed in WIPO International Publication Nos. WO 94/24140, WO94/02466 and WO 97/20824. There remains a need for effective MMP andTNF-α convertase inhibiting agents. Compounds that inhibit MMPs such ascollagenase, stromelysin and gelatinase have been shown to inhibit therelease of TNF (Gearing et al. Nature 376, 555-557 (1994), McGeehan etal., Nature 376, 558-561 (1994)).

MMPs are involved in other biochemical processes in mammals as well.Included is the control of ovulation, post-partum uterine involution,possibly implantation, cleavage of APP (β-Amyloid Precursor Protein) tothe amyloid plaque and inactivation of α₁-protease inhibitor (α₁-PI).Inhibition of these metalloproteases permits the control of fertilityand the treatment or prevention of Alzheimers Disease. In addition,increasing and maintaining the levels of an endogenous or administeredserine protease inhibitor drug or biochemical such as α₁-PI supports thetreatment and prevention of diseases such as emphysema, pulmonarydiseases, inflammatory diseases and diseases of aging such as loss ofskin or organ stretch and resiliency.

Inhibition of selected MMPs can also be desirable in other instances.Treatment of cancer and/or inhibition of metastasis and/or inhibition ofangiogenesis are examples of approaches to the treatment of diseaseswherein the selective inhibition of stromelysin (MMP-3), gelatinase(MMP-2), gelatinase B (MMP-9) or collagenase III (MMP-13) are therelatively most important enzyme or enzymes to inhibit especially whencompared with collagenase I (MMP-1). A drug that does not inhibitcollagenase I can have a superior therapeutic profile. Osteoarthritis,another prevalent disease wherein it is believed that cartilagedegradation in inflamed joints is at least partially caused by MMP-13released from cells such as stimulated chrondrocytes, may be besttreated by administration of drugs one of whose modes of action isinhibition of MMP-13. See, for example, Mitchell et al., J. Clin.Invest., 97:761-768 (1996) and Reboul et al., J. Clin. Invest.,97:2011-2019 (1996).

Inhibitors of metalloproteases are known. Examples include naturalbiochemicals such as tissue inhibitor of metalloproteinase (TIMP),α²-macroglobulin and their analogs or derivatives. These are highmolecular weight protein molecules that form inactive complexes withmetalloproteases. A number of smaller peptide-like compounds thatinhibit metalloproteases have been described. Mercaptoamide peptidylderivatives have shown ACE inhibition in vitro and in vivo. Angiotensinconverting enzyme (ACE) aids in the production of angiotensin II, apotent pressor substance in mammals and inhibition of this enzyme leadsto the lowering of blood pressure.

Thiol group-containing amide or peptidyl amide-based metalloprotease(MMP) inhibitors are known as is shown in, for example, WO95/12389,WO96/11209 and U.S. Pat. No. 4,595,700. Hydroxamate group-containing MMPinhibitors are disclosed in a number of published patent applicationssuch as WO 95/29892, WO 97/24117, WO 97/49679 and EP 0 780 386 thatdisclose carbon back-boned compounds, and WO 90/05719, WO 93/20047, WO95/09841 and WO 96/06074 that disclose hydroxamates that have a peptidylback-bones or peptidomimetic back-bones, as does the article by Schwartzet al., Progr. Med. Chem., 29:271-334(1992) and those of Rasmussen etal., Pharmacol. Ther., 75(1): 69-75 (1997) and Denis et al., Invest. NewDrugs, 15(3): 175-185 (1997).

One possible problem associated with known MMP inhibitors is that suchcompounds often exhibit the same or similar inhibitory effects againsteach of the MMP enzymes. For example, the peptidomimetic hydroxamateknown as batimastat is reported to exhibit IC₅₀ values of about 1 toabout 20 nanomolar (nM) against each of MMP-1, MMP-2, MMP-3, MMP-7, andMMP-9. Marimastat, another peptidomimetic hydroxamate was reported to beanother broad-spectrum MMP inhibitor with an enzyme inhibitory spectrumvery similar to batimastat, except that marimastat exhibited an IC₅₀value against MMP-3 of 230 nM. Rasmussen et al., Pharmacol. Ther.,75(1): 69-75 (1997).

Meta analysis of data from Phase I/II studies using marimastat inpatients with advanced, rapidly progressive, treatment-refractory solidtumor cancers (colorectal, pancreatic, ovarian, prostate) indicated adose-related reduction in the rise of cancer-specific antigens used assurrogate markers for biological activity. Although marimastat exhibitedsome measure of efficacy via these markers, toxic side effects werenoted. The most common drug-related toxicity of marimastat in thoseclinical trials was musculoskeletal pain and stiffness, often commencingin the small joints in the hands, spreading to the arms and shoulder. Ashort dosing holiday of 1-3 weeks followed by dosage reduction permitstreatment to continue. Rasmussen et al., Pharmacol. Ther., 75(1): 69-75(1997). It is thought that the lack of specificity of inhibitory effectamong the MMPs may be the cause of that effect.

In view of the importance of hydroxamate MMP inhibitor compounds in thetreatment of several diseases-and the lack of enzyme specificityexhibited by two of the more potent drugs now in clinical trials, itwould be a great benefit if hydroxamates of greater enzyme specificitycould be found. This would be particularly the case if the hydroxamateinhibitors exhibited strong inhibitory activity against one or more ofMMP-2, MMP-9 or MMP-13 that are associated with several pathologicalconditions, while at the same time exhibiting limited inhibition ofMMP-1, an enzyme that is relatively ubiquitous and as yet not associatedwith any pathological condition. The disclosure that follows describesone family of hydroxamate MMP inhibitors that exhibit those desirableactivities

BRIEF SUMMARY OF THE INVENTION

The present invention is directed to a family of molecules that amongother properties inhibit matrix metalloprotease (MMP) activity, andparticularly inhibit the activity of one or more of MMP-2, MMP-9, orMMP-13, while generally exhibiting little activity against MMP-1. Thepresent invention is also directed to processes for preparing acontemplated compound and for treating a mammal having a conditionassociated with pathological matrix metalloprotease activity.

Briefly, one embodiment of the present invention is directed to aN-hydroxy sulfonyl butanamide (hydroxamic acid) compound that can act asa matrix metalloprotease enzyme inhibitor. That compound corresponds instructure to Formula I.

wherein

R¹ is a substituent containing a 5- or 6-membered cyclohydrocarbyl,heterocyclo, aryl or heteroaryl radical bonded directly to the depictedSO₂-group and having a length greater than about the length of a fullyextended hexyl group and less than about the length of a fully extendedeicosyl group, said R¹ defining a three-dimensional volume, when rotatedabout an axis drawn through the SO₂-bonded 1-position and the 4-positionof a 6-membered ring radical or drawn through the SO₂-bonded 1-positionand the center of 3,4-bond of a 5-membered ring radical, whose widestdimension in a direction transverse to the axis of rotation isequivalent to about that of one furanyl ring to about that of two phenylrings;

R² and R³ are independently selected from the group consisting of ahydrido, C₁-C₄ hydrocarbyl, heteroaryl-C₁-C₄ hydrocarbyl, aryl-C₁-C₄hydrocarbyl, hydroxy-C₁-C₄ hydrocarbyl, C₁-C₄ hydrocarbyloxy-C₁-C₄hydrocarbyl, aryloxy-C₁-C₄ hydrocarbyl, amino-C₁-C₄ hydrocarbyl, C₁-C₄hydrocarbylthio-C₁-C₄ hydrocarbyl, C₁-C₄ hydrocarbylsulfdonyl-C₁-C₄hydrocarbyl, aminosulfonylamino-C₁-C₄ hydrocarbyl,aminocarbonylamino-C₁-C₄ hydrocarbyl, C₁-C₄hydrocarbylcarbonylamino-C₁-C₄ hydrocarbyl, aryl-C₁-C₄ hydrocarbyl,heteroaryl-C₁-C₄ hydrocarbyl and benzyloxy-C₁-C₄ hydrocarbyl, but onlyone of R² and R³ is other than hydrido or C₁-C₄ hydrocarbyl; or

R² and R³ together with the depicted carbon atom to which they arebonded form a heterocyclic ring in which the heteroatom is oxygen,sulfur or nitrogen, said heteroatom being optionally substituted withone or two oxygens when sulfur and being substituted with a moiety R⁵that is selected from the group consisting of a hydrido, C₁-C₄hydrocarbyl, C₃-C₆ cyclohydrocarbyl, C₁-C₄ carbonylhydrocarbyl, andsulfonyl C₁-C₄ hydrocarbyl group when nitrogen; and

R⁶ and R⁷ are independently selected from the group consisting of ahydrido, C₁-C₄ hydrocarbyl, heteroaryl-C₁-C₄ hydrocarbyl, aryl-C₁-C₄hydrocarbyl, hydroxy-C₁-C₄ hydrocarbyl, C₁-C₄ hydrocarbyloxy-C₁-C₄hydrocarbyl, aryloxy-C₁-C₄ hydrocarbyl, amino-C₁-C₄ hydrocarbyl, C₁-C₄hydrocarbylthio-C₁-C₄ hydrocarbyl, C₁-C₄ hydrocarbylsulfdonyl-C₁-C₄hydrocarbyl, aminosulfonylamino-C₁-C₄ hydrocarbyl,aminocarbonylamino-C₁-C₄ hydrocarbyl, C₁-C₄hydrocarbylcarbonylamino-C₁-C₄ hydrocarbyl, aryl-C₁-C₄ hydrocarbyl,heteroaryl-C₁-C₄ hydrocarbyl and benzyloxy-C₁-C₄ hydrocarbyl, but onlyone of R⁶ and R⁷ is other than hydrido or C₁-C₄ hydrocarbyl; or

R⁶ and R⁷ together with the depicted carbon atom to which they arebonded form a heterocyclic ring in which the heteroatom is oxygen,sulfur or nitrogen, said heteroatom being optionally substituted withone or two oxygens when sulfur and being substituted with a moiety R⁵that is selected from the group consisting of a hydrido, C₁-C₄hydrocarbyl, C₃-C₆ cyclohydrocarbyl, C₁-C₄ carbonylhydrocarbyl, andsulfonyl C₁-C₄ hydrocarbyl group when nitrogen;

only one of R², R³, R⁶ and R⁷ is other than hydrido, C₁-C₄ hydrocarbylor forms part of a heterocyclic ring structure as recited.

In preferred embodiments,R² is selected from the group consisting of ahydrido, C₁-C₄ hydrocarbyl, N-piperidinyl, N-piperazinyl, N-(C₁-C₄hydrocarbyl)piperazinyl, N-pyrrolidinyl, N-morpholinyl and —Y—Z group,wherein —Y is —O or —NR¹¹, wherein R¹¹ is hydrido or C₁-C₄ hydrocarbyl,and —Z is selected from the group consisting of a hydrido, C₁-C₄hydrocarbyl, benzoyl, (2-pyridinyl)methyl, (3-pyridinyl)methyl or(4-pyridinyl)methyl, 2-(morpholinyl)ethyl, 2-(piperidinyl)ethyl,2-(piperazinyl)ethyl, 2-(N-methylpiperazinyl)ethyl,2-(thiomorpholinyl)ethyl, 2-(thiomorpholinyl sulfone)ethyl,2-(succinimidyl)ethyl, 2-(hydantoinyl), 2-(3-methylhydantoinyl)ethyl,2-(N-C₁-C₄ hydrocarbylamino)ethyl, 2-[N,N-di(C₁-C₄hydrocarbyl)amino]ethyl, carboxy C₁-C₄ hydrocarbyl, piperidinyl, 2-, 3-,or 4-pyridinyl, sulfonamido, C₁-C₄ hydrocarbylsulfonyl, C₁-C₄hydrocarbylphosphonyl and C(O)—W wherein —W is selected from the groupconsisting of a hydrido, C₁-C₄ hydrocarbyl, C₁-C₄ hydrocarbyloxy—CHR¹²NH₂ wherein R¹² is the side chain of a D or L amino acid,benzyloxy, benzylamino and amino group, or R² and R³ together form aheterocyclic ring, and R⁶ and R⁷ are both either hydrido or methyl. Inone of those embodiments, a contemplated compound corresponds instructure Formula II:

wherein

Ph is a phenyl radical bonded directly to the depicted SO₂-group that isitself substituted at its own 4-position with a substituent R⁴ selectedfrom the group consisting of one other single-ringed aryl or heteroarylgroup, a C₃-C₁₄ hydrocarbyl group, a C₂-C₁₄ hydrocarbyloxy group, aphenoxy group, a thiophenoxy group, a 4-thiopyridyl group, a phenylazogroup, a phenylureido group, a nicotinamido group, an isonicotinamidogroup, a picolinamido group, an anilino group and a benzamido group;

R² is selected from the group consisting of a hydrido, C₁-C₄hydrocarbyl, N-piperidinyl, N-piperazinyl, N-(C₁-C₄hydrocarbyl)piperazinyl, N-pyrrolidinyl, N-morpholinyl and —Y—Z group,wherein —Y is —O or —NR₁₁, wherein R¹¹ is hydrido or C₁-C₄ hydrocarbyl,and —Z is selected from the group consisting of a hydrido, C₁-C₄hydrocarbyl, benzoyl, (2-pyridinyl)methyl, (3-pyridinyl)methyl or(4-pyridinyl)methyl, 2-(morpholinyl)ethyl, 2-(piperidinyl)ethyl,2-(piperazinyl)ethyl, 2-(N-methylpiperazinyl)ethyl,2-(thiomorpholinyl)ethyl, 2-(thiomorpholinyl sulfone)ethyl,2-(succinimidyl)ethyl, 2-(hydantoinyl), 2-(3-methylhydantoinyl)ethyl,2-(N-C₁-C₄ hydrocarbylamino)ethyl, 2-[N,N-di(C₁-C₄hydrocarbyl)amino]ethyl, carboxy C₁-C₄ hydrocarbyl, piperidinyl, 2-, 3-,or 4-pyridinyl, sulfonamido, C₁-C₄ hydrocarbylsulfonyl, C₁-C₄hydrocarbylphosphonyl and C(O)—W wherein —W is selected from the groupconsisting of a hydrido, C₁-C₄ hydrocarbyl, C₁-C₄ hydrocarbyloxy—CHR¹²NH₂ wherein R¹² is the side chain of a D or L amino acid,benzyloxy, benzylamino and amino group;

R³ is a hydrido or C₁-C₄ hydrocarbyl group; or

R² and R³ together with the depicted carbon atom to which they arebonded form a 6-membered heterocyclic ring in which the heteroatom isoxygen, sulfur or nitrogen, said heteroatom being optionally substitutedwith one or two oxygens when sulfur and being substituted with a moietyR⁵ that is selected from the group consisting of a hydrido, C₁-C₄hydrocarbyl, C₃-C₆ cyclohydrocarbyl, C₁-C₄ carbonylhydrocarbyl, andsulfonyl C₁-C₄ hydrocarbyl group when nitrogen.

A process for treating a host mammal having a condition associated withpathological matrix metalloprotease activity is also contemplated. Thatprocess comprises administering a compound described hereinbefore in anenzyme-inhibiting effective amount to a mammalian host having such acondition. The use of repeated administrations is particularlycontemplated.

Among the several benefits and advantages of the present invention arethe provision of compounds and compositions effective as inhibitors ofmatrix metalloproteinase activity, and the provision of such compoundsand compositions that are effective for the inhibition ofmetalloproteinases implicated in diseases and disorders involvinguncontrolled breakdown of connective tissue.

More particularly, a benefit of this invention is the provision of acompound and composition effective for inhibiting metalloproteinases,particularly MMP-13 and/or MMP-2, associated with pathologicalconditions such as, for example, rheumatoid arthritis, osteoarthritis,septic arthritis, corneal, epidermal or gastric ulceration, tumormetastasis, invasion or angiogenesis, periodontal disease, proteinuria,Alzheimer's Disease, coronary thrombosis, multiple sclerosis and bonedisease.

An advantage of the invention is the provision of a method for preparingsuch compositions. Another benefit is the provision of a method fortreating a pathological condition associated with abnormal matrixmetalloproteinase activity.

Another advantage of the invention is the provision of compounds,compositions and methods effective for treating such pathologicalconditions by selective inhibition of a metalloproteinase such as MMP-13and MMP-2 associated with such conditions with minimal side effectsresulting from inhibition of other proteinases such as MMP-1, whoseactivity is necessary or desirable for normal body function.

Still further benefits and advantages of the invention will be apparentto the skilled worker from the disclosure that follows.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

In accordance with the present invention, it has been found that certainN-hydroxy sulfonyl butanamide (hydroxamic acid) compounds, also referredto herein as sulfonyl butanhydroxamate compounds, are effective, interalia, for inhibition of matrix metalloproteinases (“MMPs”) believed tobe associated with uncontrolled or otherwise pathological breakdown ofconnective tissue. In particular, it has been found that these certainsulfonyl butanhydroxamate compounds are effective for inhibition ofcollagenase III (MMP-13) and also gelatinase A (MMP-2), which can beparticularly destructive to tissue if present or generated in abnormalquantities or concentrations, and thus exhibit a pathological activity.

Moreover, it has been discovered that many of these sulfonylbutanhydroxamate compounds are selective in the inhibition of MMPsassociated with diseased conditions without excessive inhibition ofother collagenases essential to normal bodily function such as tissueturnover and repair. More particularly, it has been found thatparticularly preferred the sulfonyl butanhydroxamate compounds areparticularly active in inhibiting of MMP-13 and/or MMP-2, while having alimited or minimal effect on MMP-1. This point is discussed in detailhereinafter and is illustrated in the Inhibition Table hereinafter.

One embodiment of the present invention is directed to a sulfonylbutanhydroxamate compound that can act as a matrix metalloproteaseenzyme inhibitor. That compound corresponds in structure to Formula I

wherein

R¹ is a substituent containing a 5- or 6-membered cyclohydrocarbyl,heterocyclo, aryl or heteroaryl radical bonded directly to the depictedSO₂-group and having a length that is equivalent to a length that isgreater than about that of a fully extended hexyl group and less thanabout that of a fully extended eicosyl group. In addition, R¹ defines athree-dimensional volume, when rotated about an axis drawn through theSO₂-bonded 1-position and the 4-position of a 6-membered ring radical ordrawn through the SO₂-bonded 1-position and the center of 3,4-bond of a5-membered ring radical, whose widest dimension in a directiontransverse to the axis of rotation is equivalent to about that of onefuranyl ring to about that of two phenyl rings;

R² and R³ are independently selected from the group consisting of ahydrido, C₁-C₄ hydrocarbyl, heteroaryl-C₁-C₄ hydrocarbyl, aryl-C₁-C₄hydrocarbyl, hydroxy-C₁-C₄ hydrocarbyl, C₁-C₄ hydrocarbyloxy-C₁-C₄hydrocarbyl, aryloxy-C₁-C₄ hydrocarbyl, amino-C₁-C₄ hydrocarbyl, C₁-C₄hydrocarbylthio-C₁-C₄ hydrocarbyl, C₁-C₄ hydrocarbylsulfdonyl-C₁-C₄hydrocarbyl, aminosulfonylamino-C₁-C₄ hydrocarbyl,aminocarbonylamino-C₁-C₄ hydrocarbyl, C₁-C₄hydrocarbylcarbonylamino-C₁-C₄ hydrocarbyl, aryl-C₁-C₄ hydrocarbyl,heteroaryl-C₁-C₄ hydrocarbyl and benzyloxy-C₁-C₄ hydrocarbyl, but onlyone of R² and R³ is other than hydrido or C₁-C₄ hydrocarbyl; or

R² and R³ together with the depicted carbon atom to which they arebonded form a heterocyclic ring in which the heteroatom is oxygen,sulfur or nitrogen, said heteroatom being optionally substituted withone or two oxygens when sulfur and being substituted with a moiety R⁵that is selected from the group consisting of a hydrido, C₁-C₄hydrocarbyl, C₃-C₆ cyclohydrocarbyl, C₁-C₄ carbonylhydrocarbyl, andsulfonyl C₁-C₄ hydrocarbyl group when nitrogen; and

R⁶ and R⁷ are independently selected from the group consisting of ahydrido, C₁-C₄ hydrocarbyl, heteroaryl-C₁-C₄ hydrocarbyl, aryl-C₁-C₄hydrocarbyl, hydroxy-C₁-C₄ hydrocarbyl, C₁-C₄ hydrocarbyloxy-C₁-C₄hydrocarbyl, aryloxy-C₁-C₄ hydrocarbyl, amino-C₁-C₄ hydrocarbyl, C₁-C₄hydrocarbylthio-C₁-C₄ hydrocarbyl, C₁-C₄ hydrocarbylsulfdonyl-C₁-C₄hydrocarbyl, aminosulfonylamino-C₁-C₄ hydrocarbyl,aminocarbonylamino-C₁-C₄ hydrocarbyl, C₁-C₄hydrocarbylcarbonylamino-C₁-C₄ hydrocarbyl, aryl-C₁-C₄ hydrocarbyl,heteroaryl-C₁-C₄ hydrocarbyl and benzyloxy-C₁-C₄ hydrocarbyl, but onlyone of R⁶ and R⁷ is other than hydrido or C₁-C₄ hydrocarbyl; or

R⁶ and R⁷ together with the depicted carbon atom to which they arebonded form a heterocyclic ring in which the heteroatom is oxygen,sulfur or nitrogen, said heteroatom being optionally substituted withone or two oxygens when sulfur and being substituted with a moiety R⁵that is selected from the group consisting of a hydrido, C₁-C₄hydrocarbyl, C₃-C₆ cyclohydrocarbyl, C₁-C₄ carbonylhydrocarbyl, andsulfonyl C₁-C₄ hydrocarbyl group when nitrogen;

only one of R², R³, R⁶ and R⁷ is other than hydrido, C₁-C₄ hydrocarbylor forms part of a heterocyclic ring structure as recited.

As noted above, an R¹ substituent contains a 5- or 6-memberedcyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical bondeddirectly to the depicted SO₂-group. An R¹ substituent also has length,width and substitution requirements that are discussed in detail below.It is noted here, however, that a single-ringed or fused ringcyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical is not itselflong enough to fulfill the length requirement. As such, thatcyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical must itself besubstituted.

Exemplary 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl orheteroaryl radicals that can constitute a portion of a R¹ substituentand are themselves substituted as discussed herein include phenyl, 2-,3-, or 4-pyridyl, 2-naththyl, 2-pyrazinyl, 2- or 5-pyrimidinyl, 2- or3-benzo(b)thienyl, 8-purinyl, 2- or 3-furyl, 2- or 3-pyrrolyl,2-imidazolyl, cyclopentyl, cyclohexyl, 2- or 3-piperidinyl, 2- or3-morpholinyl, 2- or 3-tetrahydropyranyl, 2-imidazolidinyl, 2- or3-pyrazolidinyl and the like. A phenyl radical is particularly preferredand is used illustratively herein.

When examined along its longest chain of atoms, an R¹ substituent,including its own substituent when present, has a total lengthequivalent to a length that is greater than that of a fully extendedsaturated chain of six carbon atoms (a hexyl group); i.e., a length of afully extended heptyl chain or longer, and a length that is less thanthat of a fully extended saturated chain of about 20 carbons (an eicosylgroup). Preferably, that length is equivalent to a length of a fullyextended saturated chain of about 8 to about 18 carbon atoms, eventhough many more atoms may be present in ring structures orsubstituents. This length requirement is discussed further below.

Looked at more generally, and aside from specific moieties from which itis constructed, an R¹ substituent (radical, group or moiety) has alength equivalent to that of a fully extended heptyl group or greater.Such an R¹ substituent also has a length that is less than that of afully extended eicosyl group. That is to say that a R¹ is a substituenthaving a length greater than that of a saturated six carbon chain andshorter than that of a saturated twenty carbon chain, and morepreferably, a length greater than that of a octyl group and less thanthat of a palmityl group. The radical chain lengths are measured alongthe longest linear atom chain in the radical, following the skeletalatoms of a ring where necessary. Each atom in the chain, e.g. carbon,oxygen or nitrogen, is presumed to be carbon for ease in calculation.

Such lengths can be readily determined by using published bond angles,bond lengths and atomic radii, as needed, to draw and measure a chain,or by building models using commercially available kits whose bondangles, lengths and atomic radii are in accord with accepted, publishedvalues. Radical (substituent) lengths can also be determined somewhatless exactly by presuming, as is done here, that all atoms have bondlengths of saturated carbon, that unsaturated and aromatic bonds havethe same lengths as saturated bonds and that bond angles for unsaturatedbonds are the same as those for saturated bonds, although theabove-mentioned modes of measurement are preferred. For example, a4-phenyl or 4-pyridyl group has a length of a four carbon chain, as doesa propoxy group, whereas a biphenyl group has a length of about an eightcarbon chain using a contemplated measurement mode.

In addition, an R¹ substituent, when rotated about an axis drawn throughthe SO₂-bonded 1-position and the 4-position of a 6-membered ringradical or the SO₂-bonded 1-position and through the 3,4 bond of a5-membered ring radical defines a three-dimensional volume whose widestdimension has the width equivalent to that of about one furanyl ring toabout the width of two phenyl rings in a direction transverse to thataxis to rotation.

When utilizing this width or volume criterion, a fused ring system suchas a naphthyl or purinyl radical is considered to be a 6- or 5-memberedring that is substituted at appropriate positions numbered from theSO₂-linkage that is deemed to be at the 1-position as discussed before.Thus, a 2-naphthyl substituent or an 8-purinyl substituent is anappropriately sized R¹ radical as to width when examined using the aboverotational width criterion. On the other hand, a 1-naphthyl group or a7- or 9-purinyl group is too large upon rotation and is excluded.

As a consequence of these length and width requirements, R¹ substituentssuch as 4-(phenyl)phenyl [biphenyl], 4-(4′-methoxyphenyl)phenyl,4-(phenoxy)phenyl, 4-(thiophenyl)phenyl [4-(phenylthio)phenyl],4-(phenylazo)phenyl 4-(phenylureido)phenyl, 4-(anilino)phenyl,4-(nicotinamido)phenyl, 4-(isonicotinamido)phenyl,4-(picolinamido)phenyl and 4-(benzamido)phenyl are among particularlypreferred R¹ substituents, with 4-(phenoxy)phenyl and4-(thiophenyl)phenyl being most preferred.

An SO₂-linked cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radicalis a 5- or 6-membered single-ring that is itself substituted with oneother substituent, R⁴. The SO₂-linked single-ringed cyclohydrocarbyl,heterocyclo, aryl or heteroaryl radical is R⁴-substituted at its own4-position when a 6-membered ring and at its own 3-position when a5-membered ring. The cyclohydrocarbyl, heterocyclo, aryl or heteroarylradical to which R⁴ is bonded is preferably a phenyl group, so that R¹is preferably PhR⁴ in which R⁴ is bonded at the 4-position of theSO₂-linked phenyl (Ph) radical, and in which R⁴ can itself be optionallysubstituted as is discussed hereinafter. Substitution at the 2-positionof a SO₂-linked cyclohydrocarbyl, heterocyclo, aryl or heteroaryl.radical appears to greatly lessen inhibitory potency toward MMPenzymes, and is absent from a contemplated compound.

A contemplated R⁴ substituent can be a single-ringed cyclohydrocarbyl,heterocyclo, aryl or heteroaryl group or another substituent having achain length of 3 to about 14 carbon atoms such as a hydrocarbyl orhydrocarbyloxy group [e.g., C₃-C₁₄ hydrocarbyl or O-C₂-C₁₄ hydrocarbyl],a phenyl group, a phenoxy group [—OC₆H₅], a thiophenoxy group[phenylsulfanyl; —SC₆H₅], an anilino group [—NHC₆H₅], a phenylazo group[—N₂C₆H₅], a phenylureido group [aniline carbonylamino; —NHC(O)NH—C₆H₅],a benzamido group [—NHC(O)C₆H₅], a nicotinamido group [3-NHC(O)C₅H₄N],an isonicotinamido group [4-NHC(O)C₅H₄N], or a picolinamido group[2-NHC(O)C₅H₄N]. As noted before in conjunction with the discussion ofR¹, most preferred R⁴ substituents are phenoxy and thiophenoxy groupsthat are preferably themselves free of substitution. Additionallycontemplated R⁴ substituent groups include a heterocyclo,heterocyclohydrocarbyl, arylhydrocarbyl, arylheterocyclohydrocarbyl,heteroarylhydrocarbyl, heteroarylheterocyclohydrocarbyl,arylhydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl,hydrocarboylhydrocarbyl, arylhydrocarboylhydrocarbyl,arylcarbonylhydrocarbyl, arylazoaryl, arylhydrazinoaryl,hydrocarbylthiohydrocarbyl, hydrocarbylthioaryl, arylthiohydrocarbyl,heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl,arylhydrocarbylthiohydrocarbyl, arylhydrocarbylthioaryl,arylhydrocarbylamino, heteroarylhydrocarbylamino, and a heteroarylthiogroup.

A contemplated R⁴ substituent can itself also be substituted with one ormore substituent radicals at the meta- or para-position or both of asix-membered ring with a single atom or a substituent containing alongest chain of up to ten atoms, excluding hydrogen. Exemplarysubstituent radicals include a halo, hydrocarbyl, hydrocarbyloxy, nitro,cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy,mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino,arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino,heteroarylhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl,heterocyclooxy, hydroxycarbonylhydrocarbyl, heterocyclothio,heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio,cyclohydrocarbylamino, heteroarylhydrocarbyloxy,heteroarylhydrocarbylthio, heteroarylhydrocarbylamino,arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino,heterocyclic, heteroaryl, hydroxycarbonyl-hydrocarbyloxy,alkoxycarbonylalkoxy, hydrocarbyloyl, arylcarbonyl, arylhydrocarbyloyl,hydrocarboyloxy, arylhydrocarboyloxy, hydroxyhydrocarbyl,hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio,hydrocarbyloxycarbonyl, hydroxycarbonylhydrocarbyloxy,hydrocarbyloxy-carbonylhydrocarbyl,hydrocarbylhydroxycarbonyl-hydrocarbylthio,hydrocarbyloxycarbonylhydrocarbyloxy,hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino,arylcarbonylamino, cyclohydrocarbylcarbonylamino,heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino,heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino,heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino,arylhydrocarbylsulfonylamino, heteroarylsulfonylamino,heteroarylhydrocarbyl-sulfonylamino, cyclohydrocarbylsulfonylamino,heterocyclohydrocarbylsulfonylamino and N-monosubstituted orN,N-disubstituted aminohydrocarbyl group wherein the substituent(s) onthe nitrogen are selected from the group consisting of hydrocarbyl,aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl,hydrocarbyloxycarbonyl, and hydrocarboyl, or wherein the nitrogen andtwo substituents attached thereto form a 5- to 8-membered heterocyclicor heteroaryl ring group.

Thus, initial studies indicate that so long as the length, substitutionand width (volume upon rotation) requirements of an SO₂-linked R¹substituent discussed herein are met, an R¹ substituent can be extremelyvaried.

A particularly preferred R⁴ substituent of an SO₂-linked Ph group is asingle-ringed aryl or heteroaryl, phenoxy, thiophenoxy, phenylazo,phenylureido, nicotinamido, isonicotinamido, picolinamido, anilino orbenzamido group that is unsubstituted or is itself substituted(optionally substituted) at the para-position when a 6-membered ring orthe 3-position when a 5-membered ring. Here, single atoms such ashalogen moieties or substituents that contain one to a chain of aboutten atoms other than hydrogen such as C₁-C₁₀ hydrocarbyl, C₁-C₉hydrocarbyloxy or carboxyethyl groups can be used.

Exemplary particularly preferred substituted PhR⁴ (particularlypreferred substituted R¹) substituents include biphenyl,4-phenoxyphenyl, 4-thiophenoxyphenyl, 4-benzamidophenyl, 4-phenylureido,4-anilinophenyl, 4-nicotinamido, 4-isonicotinamido, and 4-picolinamido.Exemplary particularly preferred R⁴ groups contain a 6-membered aromaticring and include a phenyl group, a phenoxy group, a thiophenoxy group, aphenylazo group, a phenylureido group, an anilino group, a nicotinamidogroup, an isonicotinamido group, a picolinamido group and a benzamidogroup.

More specifically, a particularly preferred sulfonyl butanhydroxamatecompounds has an R⁴ substituent that is a phenyl group, a phenoxy group,a thiophenoxy group, a phenylazo group, a phenylureido group, an anilinogroup, a nicotinamido group, an isonicotinamido group, a picolinamidogroup or a benzamido group that is itself optionally substituted at itsown meta or para-position or both with a moiety that is selected fromthe group consisting of a halogen, a C₁-C₉ hydrocarbyloxy (—O—C₁-C₉hydrocarbyl) group, a C₁-C₁₀ hydrocarbyl group, a di-C₁-C₉hydrocarbylamino [—N(C₁-C₉ hydrocarbyl)(C₁-C₉ hydrocarbyl)] group, acarboxyl C₁-C₈ hydrocarbyl (C₁-C₈ hydrocarbyl-CO₂H) group, a C₁-C₄hydrocarbyloxy carbonyl C₁-C₄ hydrocarbyl [C₁-C₄hydrocarbyl-O—(CO)—C₁-C₄ hydrocarbyl] group, a C₁-C₄hydrocarbyloxycarbonyl C₁-C₄ hydrocarbyl [C₁-C₄ hydrocarbyl(CO)—O—C₁-C₄hydrocarbyl] group and a C₁-C₈ hydrocarbyl carboxamido [—NH(CO)-C₁-C₈hydrocarbyl] group, or is substituted at the meta- and para-positions bytwo methyl groups or by a C₁-C₂ alkylenedioxy group such as amethylenedioxy group.

Inasmuch as a contemplated SO₂-linked cyclohydrocarbyl, heterocyclo,aryl or heteroaryl radical is itself preferably substituted with a6-membered aromatic ring, two nomenclature systems are used togetherherein for ease in understanding substituent positions. The first systemuses position numbers for the ring directly bonded to the SO₂-group,whereas the second system uses ortho, meta or para for the position ofone or more substituents of a 6-membered ring bonded to a SO₂-linkedcyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical. When a R⁴substituent is other than a 6-membered ring, substituent positions arenumbered from the position of linkage to the aromatic or heteroaromaticring. Formal chemical nomenclature is used in naming particularcompounds.

Thus, the 1-position of an above-discussed SO₂-linked cyclohydrocarbyl,heterocyclo, aryl or heteroaryl radical is the position at which theSO₂-group is bonded to the ring. The 4- and 3-positions of ringsdiscussed here are numbered from the sites of substituent bonding fromthe SO₂-linkage as compared to formalized ring numbering positions usedin heteroaryl nomenclature.

R² and R³ are independently selected from the group consisting of ahydrido, C₁-C₄ hydrocarbyl, heteroaryl-C₁-C₄ hydrocarbyl, aryl-C₁-C₄hydrocarbyl, hydroxy-C₁-C₄ hydrocarbyl, C₁-C₄ hydrocarbyloxy-C₁-C₄hydrocarbyl, aryloxy-C₁-C₄ hydrocarbyl, amino-C₁-C₄ hydrocarbyl, C₁-C₄hydrocarbylthio-C₁-C₄ hydrocarbyl, C₁-C₄ hydrocarbylsulfonyl-C₁-C₄hydrocarbyl, aminosulfonylamino-C₁-C₄ hydrocarbyl,aminocarbonylamino-C₁-C₄ hydrocarbyl, C₁-C₄hydrocarbylcarbonylamino-C₁-C₄ hydrocarbyl and benzyloxy-C₁-C₄hydrocarbyl. However, only one of R² and R³ is other than hydrido orC₁-C₄ hydrocarbyl, with hydrido being the preferred substituent.

Alternatively, R² and R³ together with the depicted carbon atom to whichthey are bonded form a heterocyclic ring, preferably a six-memberedring, in which the heteroatom is oxygen, sulfur or nitrogen. Thatheteroatom is optionally substituted with one or two oxygens when sulfurand is substituted with a moiety R⁵ that is selected from the groupconsisting of a hydrido, C₁-C₄ hydrocarbyl, C₃-C₆ cyclohydrocarbyl,C₁-C₄ carbonylhydrocarbyl, and sulfonyl C₁-C₄ hydrocarbyl group whennitrogen.

R⁶ and R⁷ are independently selected from the group consisting of ahydrido, C₁-C₄ hydrocarbyl, heteroaryl-C₁-C₄ hydrocarbyl, aryl-C₁-C₄hydrocarbyl, hydroxy-C₁-C₄ hydrocarbyl, C₁-C₄ hydrocarbyloxy-C₁-C₄hydrocarbyl, aryloxy-C₁-C₄ hydrocarbyl, amino-C₁-C₄ hydrocarbyl, C₁-C₄hydrocarbylthio-C₁-C₄ hydrocarbyl, C₁-C₄ hydrocarbylsulfdonyl-C₁-C₄hydrocarbyl, aminosulfonylamino-C₁-C₄ hydrocarbyl,aminocarbonylamino-C₁-C₄ hydrocarbyl, C₁-C₄hydrocarbylcarbonylamino-C₁-C₄ hydrocarbyl and benzyloxy-C₁-C₄hydrocarbyl. Again, only one of R⁶ and R⁷ is other than hydrido or C₁-C₄hydrocarbyl, with both substituents preferably being either hydrido ormethyl.

Alternatively, R⁶ and R⁷ together with the depicted carbon atom to whichthey are bonded form a heterocyclic ring in which the heteroatom isoxygen, sulfur or nitrogen. That heteroatom is optionally substitutedwith one or two oxygens when sulfur and is substituted with a moiety R⁵that is selected from the group consisting of a hydrido, C₁-C₄hydrocarbyl, C₃-C₆ cyclohydrocarbyl, C₁-C₄ carbonylhydrocarbyl, andsulfonyl C₁-C₄ hydrocarbyl group when nitrogen.

Preferred R⁶ and R⁷ substituents and heterocyclic rings are the same asthose noted above for R² and R³, and therefore will not be repeatedhere.

It is to be noted that only one of R², R³, R⁶ and R⁷ is other thanhydrido, C₁-C₄ hydrocarbyl or forms part of a heterocyclic ringstructure as recited. Thus, the presence of two substituents on twoadjacent carbon atoms other than hydrido or C₁-C₄ hydrocarbyl is notcontemplated, nor is the presence of two heterocyclic rings on adjacentcarbons.

In preferred embodiments, R⁶ and R⁷ are preferably both either hydridoor methyl.

In one particularly preferred embodiment, a contemplated compoundcorresponds in structure to Formula II, wherein preferred R² and R³substituents are as defined below, and R¹ is PhR⁴ wherein Ph is phenylsubstituted at the 4-position with substituent R⁴ that is definedhereinabove. It is noted that preferred R² and R³ substituents need notbe present only when R¹ is PhR⁴, and can be present with any R¹substituent.

In preferred embodiments, an R² substituent is selected from the groupconsisting of a hydrido, C₁-C₄ hydrocarbyl, N-piperidinyl,N-piperazinyl, N-(C₁-C₄ hydrocarbyl)piperazinyl, N-pyrrolidinyl,N-morpholinyl and a —Y—Z group, wherein —Y is —O or —NR¹¹, R¹¹ ishydrido or C₁-C₄ hydrocarbyl, and —Z is selected from the groupconsisting of a hydrido, C₁-C₄ hydrocarbyl, benzoyl,(2-pyridinyl)methyl, (3-pyridinyl)methyl or (4-pyridinyl)methyl,2-(morpholinyl)ethyl, 2-(piperidinyl)ethyl, 2-(piperazinyl)ethyl,2-(N-methylpiperazinyl)ethyl, 2-(thiomorpholinyl)ethyl,2-(thiomorpholinyl sulfone)ethyl, 2-(succinimidyl)ethyl,2-(hydantoinyl), 2-(3-methylhydantoinyl)ethyl, 2-(N-C₁-C₄hydrocarbylamino)ethyl, 2-[N,N-di(C₁-C₄ hydrocarbyl)amino]ethyl, carboxyC₁-C₄ hydrocarbyl, piperidinyl, 2-, 3-, or 4-pyridinyl, sulfonamido,C₁-C₄ hydrocarbylsulfonyl, C₁-C₄ hydrocarbylphosphonyl and C(O)—Wwherein —W is selected from the group consisting of a hydrido, C₁-C₄hydrocarbyl, C₁-C₄ hydrocarbyloxy —CHR¹²NH₂ wherein R¹² is the sidechain of a D or L amino acid, benzyloxy, benzylamino and amino group.Thus, where —Y is —O and —Z is hydrido, R² (—Y—Z) is hydroxyl.Similarly, where —Y is NH and —Z is hydrido, R² is amino (—NH₂).

Exemplary amino acid side chains are those of the naturally occurring Lamino acids that can be present in D or L configuration or a mixturethereof. The side chains of the so-called modified and unusual aminoacids listed in 37 C.F.R § 1.822 are also contemplated here, and thoseside chains can be present in a D or L configuration or as a mixture.

Preferably, R³ is a hydrido or C₁-C₄ hydrocarbyl group. More preferably,R³ is hydrido.

Alternatively, R² and R³ together with the depicted carbon atom to whichthey are bonded form a 6-membered heterocyclic ring in which theheteroatom is oxygen, sulfur or nitrogen. That heteroatom can beoptionally substituted with one or two oxygens when sulfur and can beoptionally substituted with a moiety, R⁵, selected from the groupconsisting of a C₁-C₄ hydrocarbyl, C₃-C₆ cyclohydrocarbyl such ascyclopropyl, cyclobutyl, cyclopentenyl and cyclohexenyl, C₁-C₄carbonylhydrocarbyl such as formyl, acetyl, acryloyl, and butyryl, andsulfonyl C₁-C₄ hydrocarbyl group such as methylsulfonyl, ethylsulfonyland the like when nitrogen. Thus, R² and R³ together with theirjointly-bonded carbon atom can form a 4-tetrahydrothiopyranyl group, itscorresponding sulfoxide or sulfone, a 4-piperidinyl or a4-tetrahydropyranyl group. When present, the 4-piperidinyl group can beN-substituted with an above-described R⁵ substituent.

When R³ is hydrido,as is more preferred, particularly preferred R²groups include amino, hydroxyl, 2-, 3- and 4-pyridylmethyl,N-pyrrolidinylmethyl and N-piperidinyl. Where R² and R³ together withtheir jointly-bonded carbon atom form a six-membered heterocyclic ring,that heteroatom is preferably nitrogen that is optionally substituted asdiscussed before.

The length of an R¹ substituent bonded to the SO₂ group is believed toplay a role in the overall activity of a contemplated inhibitor compoundagainst MMP enzymes generally. Thus, a compound having an R¹ substituentthat is shorter in length than a heptyl group, e.g., a 4-methoxyphenylgroup (compound of Example 6), typically exhibits moderate to poorinhibitory activity against all of the MMP enzymes, whereas compoundswhose R¹ substituents have a length of about an heptyl chain or longer,e.g., a 4-phenoxyphenyl group (compound of Example 5) that has a lengthof about a nine-carbon chain, typically exhibit good to excellentpotencies against MMP-13 or MMP-2 and also selectivity against MMP-1.Exemplary data are provided in the Inhibition Table hereinafter in whichthe activities of the above two compounds can be compared.

The data of that Table also illustrate that compounds having an R³ groupthat is hydrido and a nitrogen-containing R² substituent areparticularly effective inhibitors of the activity of MMP-2, whilemaintaining minimal activity against MMP-1.

In view of the above-discussed preferences, compounds corresponding instructure to particular formulas constitute particularly preferredembodiments.

In one of those embodiments, a contemplated compound corresponds instructure to Formula II, below, wherein preferred R², R³ substituentsand PhR⁴ are as defined above.

A compound of Formula II is preferably present in thestereoconfiguration of Formula IIA, below

In yet another group of preferred compounds, R² and R³ together with thecarbon atom to which they are bonded form a six-membered heterocyclicring whose heteroatom, X, is O, S, S(O), S(O₂) or NR⁵, e.g., a4-piperidinyl, tetrahydropyranyl or tetrahydrothiopyranyl group. Thenitrogen of the 4-piperidinyl group is substituted with a moiety R⁵selected from the group consisting of a hydrido, C₁-C₄ hydrocarbyl,C₃-C₆ cyclohydrocarbyl, C₁-C₄ carbonylhydrocarbyl, and a sulfonyl C₁-C₄hydrocarbyl group. The R⁶ and R⁷ substituents here are both a hydrido orC₁-C₄ hydrocarbyl group, preferably methyl. Those preferred compoundscorrespond in structure generally and specifically to Formulas III andIV, respectively

Following the preference that each of R⁶ and R⁷ be methyl, and thepreference that R¹ be PhR⁴, which in turn is phenpoxyphenyl or4-thiophenoxyphenyl, another particularly preferred compound correspondsin structure to Formula V,below

The preferred stereoconfiguration of a compound of Formula V isillustrated in Formula VA, below

Taking in to consideration the further preference that R³ be a hydridogroup, a presently most preferred compound corresponds instereoconfiguration to Formula VI, below

In another of those embodiments in which the preference for R⁶ and R⁷both being hydrido, a contemplated compound corresponds in structure toFormula VII, below, wherein R², R³ and PhR⁴ are as defined above.

A above compound of this embodiment preferably has thestereoconfiguration shown in Formula VIIA, below

In a further group of preferred compounds of this embodiment, R² and R³together with the carbon atom to which they are bonded form asix-membered heterocyclic ring whose heteroatom, X, is O, S, S(O), S(O₂)or NR⁵, e.g., a 4-piperidinyl, tetrahydropyranyl ortetrahydrothiopyranyl group. The nitrogen atom of the 4-piperidinylgroup is substituted with a moiety R⁵ selected from the group consistingof a hydrido, C₁-C₄ hydrocarbyl, C₃-C₆ cyclohydrocarbyl, C₁-C₄carbonylhydrocarbyl, and a sulfonyl C₁-C₄ hydrocarbyl group. Thosepreferred compounds correspond in structure generally and specificallyto Formulas VIII and IX, respectively, below

The word “hydrocarbyl” is used herein as a short hand term to includestraight and branched chain aliphatic as well as alicyclic groups orradicals that contain only carbon and hydrogen. Thus, alkyl, alkenyl andalkynyl groups are contemplated, whereas aromatic hydrocarbons such asphenyl and naphthyl groups, which strictly speaking are also hydrocarbylgroups, are referred to herein as aryl groups or radicals, as discussedhereinafter. Where a specific aliphatic hydrocarbyl substituent group isintended, that group is recited; i.e., C₁-C₄ alkyl, methyl or dodecenyl.Exemplary hydrocarbyl groups contain a chain of 1 to about 12 carbonatoms, and preferably one to about 10 carbon atoms.

A particularly preferred hydrocarbyl group is an alkyl group. As aconsequence, a generalized, but more preferred substituent can berecited by replacing the descriptor “hydrocarbyl” with “alkyl” in any ofthe substituent groups enumerated herein.

Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyland the like. Examples of suitable alkenyl radicals include ethenyl(vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl,1-butenyl, 2-butenyl, 3-butenyl, decenyl and the like. Examples ofalkynyl radicals include ethynyl, 2-propynyl, 3-propynyl, decynyl,1-butynyl, 2-butynyl, 3-butynyl, and the like.

Usual chemical suffix nomenclature is followed when using the word“hydrocarbyl” except that the usual practice of removing the terminal“yl” and adding an appropriate suffix is not always followed because ofthe possible similarity of a resulting name to one or more substituents.Thus, a hydrocarbyl ether is referred to as a “hydrocarbyloxy” grouprather than a “hydrocarboxy” group as may possibly be more proper whenfollowing the usual rules of chemical nomenclature. On the other hand, ahydrocarbyl group containing a carbonyl group is referred to as ahydrocarboyl group inasmuch as there is no ambiguity in using thatsuffix. As a skilled worker will understand, a substituent that cannotexist such as a C₁ alkenyl group is not intended to be encompassed bythe word “hydrocarbyl”.

The term “carbonyl”, alone or in combination, means a —C(═O)— groupwherein the remaining two bonds (valences) are independentlysubstituted. The term “thiol” or “sulfhydryl”, alone or in combination,means a —SH group. The term “thio” or “thia”, alone or in combination,means a thiaether group; i.e., an ether group wherein the ether oxygenis replaced by a sulfur atom.

The term “amino”, alone or in combination, means an amine or —NH₂ group,whereas the term mono-substituted amino, alone or in combination, meansa substituted amine —N(H)(substituent) group wherein one hydrogen atomis replaced with a substituent, and disubstituted amine means a—N(substituent)2 wherein two hydrogen atoms of the amino group arereplaced with independently selected substituent groups. Amines, aminogroups and amides are classes that can be designated as primary (I°),secondary (II°) or tertiary (III°) or unsubstituted, mono-substituted ordi-substituted depending on the degree of substitution of the aminonitrogen. Quaternary amine (IV°) means a nitrogen with four substituents(—N+ (substituent)₄) that is positively charged and accompanied by acounter ion or N-oxide means one substituent is oxygen and the group isrepresented as (—N+ (substituent)₃—O³¹); i.e., the charges areinternally compensated.

The term “cyano”, alone or in combination, means a —C-triple bond-N(—CN) group. The term “azido”, alone or in combination, means a—N-double bond-N-double bond-N— (—N═N═N—) group.

The term “hydroxyl”, alone or in combination, means a —OH group. Theterm “nitro”, alone or in combination, means a —NO₂ group.

The term “azo”, alone or in combination, means a —N═N— group wherein thebonds at the terminal positions are independently substituted. The term“hydrazino”, alone or in combination, means a —NH-NH— group wherein theremaining two bonds (valences) are independently substituted. Thehydrogen atoms of the hydrazino group can be replaced, independently,with substituents and the nitrogen atoms can form acid addition salts orbe quaternized.

The term “sulfonyl”, alone or in combination, means a —S(O)₂— groupwherein the remaining two bonds (valences) can be independentlysubstituted. The term “sulfoxido”, alone or in combination, means a—S(═O)₁— group wherein the remaining two bonds (valences) can beindependently substituted. The term “sulfonylamide”, alone or incombination, means a —S(═O)₂—N═ group wherein the remaining three bonds(valences) are independently substituted. The term “sulfinamido”, aloneor in combination, means a —S(═O)₁N═ group wherein the remaining threebonds (valences) are independently substituted. The term “sulfenamide”,alone or in combination, means a —S—N═ group wherein the remaining threebonds (valences) are independently substituted.

The term “hydrocarbyloxy”, alone or in combination, means an hydrocarbylether radical wherein the term hydrocarbyl is as defined above. Examplesof suitable hydrocarbyl ether radicals include methoxy, ethoxy,n-propoxy, isopropoxy, allyloxy, n-butoxy, iso-butoxy, sec-butoxy,tert-butoxy and the like. The term “cyclohydrocarbyl”, alone or incombination, means a hydrocarbyl radical that contains 3 to about 8carbon atoms, preferably from about 3 to about 6 carbon atoms, and iscyclic. The term “cyclohydrocarbylhydrocarbyl” means an hydrocarbylradical as defined above which is substituted by a cyclohydrocarbyl asalso defined above. Examples of such cyclohydrocarbylhydrocarbylradicals include cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexylcyclooctynyl and the like.

The term “aryl”, alone or in combination, means a phenyl or naphthylradical that optionally carries one or more substituents selected fromhydrocarbyl, hydrocarbyloxy, halogen, hydroxy, amino, nitro and thelike, such as phenyl, p-tolyl, 4-methoxyphenyl, 4-(tert-butoxy)phenyl,4-fluorophenyl, 4-chlorophenyl, 4-hydroxyphenyl, and the like. The term“arylhydrocarbyl”, alone or in combination, means an hydrocarbyl radicalas defined above in which one hydrogen atom is replaced by an arylradical as defined above, such as benzyl, 2-phenylethyl and the like.The term “arylhydrocarbyloxycarbonyl”, alone or in combination, means aradical of the formula —C(O)—O— arylhydrocarbyl in which the term“arylhydrocarbyl” has the significance given above. An example of anarylhydrocarbyloxycarbonyl radical is benzyloxycarbonyl. The term“aryloxy” means a radical of the formula aryl-O— in which the term arylhas the significance given above. The term “aromatic ring” incombinations such as substituted-aromatic ring sulfonamide,substituted-aromatic ring sulfinamide or substituted-aromatic ringsulfenamide means aryl or heteroaryl as defined above.

The terms “hydrocarbyloyl” or “hydrocarbylcarbonyl”, alone or incombination, mean an acyl radical derived from an hydrocarbylcarboxylicacid, examples of which include acetyl, propionyl, acryloyl, butyryl,valeryl, 4-methylvaleryl, and the like. The term“cyclohydrocarbylcarbonyl” means an acyl group derived from a monocyclicor bridged cyclohydrocarbylcarboxylic acid such as cyclopropanecarbonyl,cyclohexenecarbonyl, adamantanecarbonyl, and the like, or from abenz-fused monocyclic cyclohydrocarbylcarboxylic acid that is optionallysubstituted by, for example, a hydrocarbyloylamino group, such as1,2,3,4-tetrahydro-2-naphthoyl,2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl. The terms“arylhydrocarbyloyl” or “arylhydrocarbylcarbonyl” mean an acyl radicalderived from an aryl-substituted hydrocarbylcarboxylic acid such asphenylacetyl, 3-phenylpropenyl (cinnamoyl), 4-phenylbutyryl,(2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, 4-aminocinnamoyl,4-methoxycinnamoyl and the like.

The terms “aroyl” or “arylcarbonyl” means an acyl radical derived froman aromatic carboxylic acid. Examples of such radicals include aromaticcarboxylic acids, an optionally substituted benzoic or naphthoic acidsuch as benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl,4-(benzyloxycarbonyl)benzoyl, 2-naphthoyl, 6-carboxy-2 naphthoyl,6-(benzyloxycarbonyl)-2-naphthoyl, 3-benzyloxy-2-naphthoyl,3-hydroxy-2-naphthoyl, 3-(benzyloxyformamido)-2-naphthoyl, and the like.

The heterocyclyl (heterocyclo) or heterocyclohydrocarbyl portion of aheterocyclylcarbonyl, heterocyclyloxycarbonyl,heterocyclylhydrocarbyloxycarbonyl, or heterocyclohydrocarbyl group orthe like is a saturated or partially unsaturated monocyclic, bicyclic ortricyclic heterocycle that contains one to four hetero atoms selectedfrom nitrogen, oxygen and sulphur, which is optionally substituted onone or more carbon atoms by a halogen, alkyl, alkoxy, oxo group, and thelike, and/or on a secondary nitrogen atom (i.e., —NH—) by anhydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloyl, aryl orarylhydrocarbyl or on a tertiary nitrogen atom (i.e. ═N—) by oxido andthat is attached via a carbon atom. The tertiary nitrogen atom withthree substituents can also form a N-oxide [═N(O)—] group. Examples ofsuch heterocyclyl groups are pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, thiamorpholinyl, and the like.

The heteroaryl portion of a heteroaroyl, heteroaryloxycarbonyl, or aheteroarylhydrocarbyloyl (heteroarylhydrocarbyl carbonyl) group or thelike is an aromatic monocyclic, bicyclic, or tricyclic heterocycle thatcontains the hetero atoms and is optionally substituted as defined abovewith respect to the definition of heterocyclyl. A “heteroaryl” group isan aromatic heterocyclic ring substituent that can contain one, two,three or four atoms in the ring that are other than carbon. Thoseheteroatoms can be nitrogen, sulfur or oxygen. A heteroaryl group cancontain a single five- or 6-membered ring or a fused ring system thatcontains two 6-membered rings or a five- and a 6-membered ring.Exemplary heteroaryl groups include 6-membered ring substituents such aspyridyl, pyrazyl, pyrimidinyl, and pyridazinyl; 5-membered ringsubstituents such as 1,3,5-, 1,2,4- or 1,2,3-triazinyl, imidazyl,furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-,1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl and isothiazolyl groups ;six/5-membered fused ring substituents such as benzothiofuranyl,isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl andanthranilyl groups ; and six/6-membered fused rings such as1,2-,.1,4-,.2,3- and 2,1-benzopyronyl, quinolinyl, isoquinolinyl,cinnolinyl, quinazolinyl, and 1,4-benzoxazinyl groups.

The term “cyclohydrocarbylhydrocarbyloxy-carbonyl” means an acyl groupderived from a cyclohydrocarbylhydrocarbyloxycarboxylic acid of theformula cyclohydrocarbylhydrocarbyl-O—COOH whereincyclohydrocarbylhydrocarbylhas the significance given above. The term“aryloxyhydrocarbyloyl” means an acyl radical of the formulaaryl-O—hydrocarbyloyl wherein aryl and hydrocarbyloyl have thesignificance given above. The term “heterocyclyloxycarbonyl” means anacyl group derived from heterocyclyl-O—COOH wherein heterocyclyl is asdefined above. The term “heterocyclylhydrocarbyloyl” is an acyl radicalderived from a heterocyclyl-substituted hydrocarbylcarboxylic acidwherein heterocyclyl has the significance given above. The term“heterocyclylhydrocarbyloxycarbonyl” means an acyl radical derived froma heterocyclyl-substituted hydrocarbyl-O—COOH wherein heterocyclyl hasthe significance given above. The term “heteroaryloxycarbonyl” means anacyl radical derived from a carboxylic acid represented byheteroaryl-O—COOH wherein heteroaryl has the significance given above.

The term “aminocarbonyl” alone or in combination, means anamino-substituted carbonyl (carbamoyl) group derived from anamino-substituted carboxylic acid wherein the amino group can be aprimary, secondary or tertiary amino group containing substituentsselected from hydrogen, hydrocarbyl, aryl, aralkyl, cyclohydrocarbyl,cyclohydrocarbylhydrocarbyl radicals and the like. The term“aminohydrocarbyloyl” means an acyl group derived from anamino-substituted hydrocarbylcarboxylic acid wherein the amino group canbe a primary, secondary or tertiary amino group containing substituentsindependently selected from hydrogen, alkyl, aryl, aralkyl,cyclohydrocarbyl, cyclohydrocarbylhydrocarbyl radicals and the like.

The term “halogen” means fluorine, chlorine, bromine or iodine. The term“halohydrocarbyl” means a hydrocarbyl radical having the significance asdefined above wherein one or more hydrogens are replaced with a halogen.Examples of such halohydrocarbyl radicals include chloromethyl,1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl,1,1,1-trifluoroethyl and the like. The term perfluorohydrocarbyl means ahydrocarbyl group wherein each hydrogen has been replaced by a fluorineatom. Examples of such perfluorohydrocarbyl groups, in addition totrifluoromethyl above, are perfluorobutyl, perfluoroisopropyl,perfluorododecyl and perfluorodecyl.

Table 1 through Table 37, below, show several contemplated N-hydroxysulfonyl butanamide compounds as structural formulas that illustratesubstituent groups. Each group of compounds is illustrated by a genericformula, followed by a series of preferred moieties or groups thatconstitute various substituents that can be attached at the positionclearly shown in the generic structure. The substituent symbols, e.g.,R¹, are as shown in each Table. One bond (straight line) is shown withthose substituents to indicate the respective positions of attachment inthe illustrated compound. This system is well known in the chemicalcommunication arts and is widely used in scientific papers andpresentations.

TABLE 1

Example -R¹ 1

2

3

4

5

6

7

8

9

10

TABLE 2

Example -R¹ 1

2

3

4

5

6

7

8

9

10

TABLE 3

Example R¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 4

Example R¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 5

TABLE 6

TABLE 7

TABLE 8

TABLE 9

TABLE 10

TABLE 11

TABLE 12

TABLE 13

TABLE 14

TABLE 15

TABLE 16

TABLE 17

Example —X 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

TABLE 18

Example —X 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

TABLE 19

Example X 1

2

3

4

5

6

7

8

9

10

11

TABLE 20

Example R¹ R² 1 —H —H 2 —H —CH₃ 3 —CH₃ —CH₃ 4 —H —OH 5 —CH₃ —OH 6 —CH₃—NH₂ 7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 21

Example R¹ R² X Ar 1

O

2

O

3

O

4

O

5

O

6

O

7

O

8

O

9

S

10

S

TABLE 22

Example —R¹ 1

2

3

4

5

6

7

8

9

10

TABLE 23

TABLE 24

TABLE 25

TABLE 26

TABLE 27

TABLE 28

TABLE 29

TABLE 30

Example X 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

TABLE 31

Example X 1

2

3

4

5

6

7

8

9

10

11

TABLE 32

Example R¹ R² 1 —H —H 2 —H —CH₃ 3 —CH₃ —CH₃ 4 —H —OH 5 —CH₃ —OH 6 —CH₃—NH₂ 7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 33

Example —R¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 34

TABLE 35

TABLE 36

TABLE 37

Preparation of Useful Compounds

Compounds of the invention can be produced in accordance with thefollowing generic synthetic Schemes A-D. It is noted that the numbersshown on R groups these schemes, except in Scheme D, are different fromthose utilized in structural formulas having Roman numerals. Thatdifference in numbering is to illustrate the generality of thesesynthesis schemes. Specific synthetic schemes that illustrate thepreparation of specific compounds follow hereinafter.

The above syntheses, as with all of the reactions discussed herein, canbe carried out under a dry inert atmosphere such a nitrogen or argon ifdesired. Selected reactions known to those skilled in the art, can becarried out under a dry atmosphere such as dry air whereas othersynthetic steps, for example, aqueous acid or base ester or amidehydrolyses, can be carried out under laboratory air.

The compounds of this invention are described above. This descriptionincludes 4-sulfonehydroxamates and hydroxamate derivatives as definedwherein 4 refers to the position of the sulfonyl group removed from thecarbonyl group of the hydroxamic acid group. The placement of thatsulfur can also shown by using the terms alpha ( ), beta ( ), gamma ( )or omega ( ) wherein alpha is the 2-position relative to the carboxyl orcarboxyl derivative carbonyl, beta is the 3- position relative to thecarboxyl or carboxyl derivative carbonyl, gamma is the 4- positionrelative to the carboxyl or carboxyl derivative carbonyl and omega isthe last position relative to the carboxyl or carboxyl derivative. Omegais a general term that denotes the last position in a chain withoutregard to the length of the chain.

As non-limiting examples, oxidations, reductions, organometallicadditions, hydrolyses, SN₂ reactions, conjugate additions, carbonyladditions, aromatic displacements and the like can be included. A personskilled in the art can apply the reactions to these compounds or readilyadapt or change synthetic procedures to a specific example as required.

In general, the choices of starting material and reaction conditions canvary as is well know to those skilled in the art. Usually, no single setof conditions is limiting because variations can be applied as requiredand selected by one skilled in the art. Conditions can also be selectedas desired to suit a specific purpose such as small scale preparationsor large scale preparations. In either case, the use of less safe orless environmentally sound materials or reagents is usually beminimized. Examples of such less desirable materials are diazomethane,diethyl ether, heavy metal salts, dimethyl sulfide, chloroform, benzeneand the like.

Various reactions illustrated in the above Schemes can be base mediatedby the use of catalytic amounts of some bases or carried out with anequivalent or more of a base by the addition of an additional reagent orthe thiol reagent can be a preformed thiol salt such as the sodium saltof a thiophenol. Bases that can be used include, for example, metalhydroxides such as sodium, potassium, lithium or magnesium hydroxide,oxides such as those of sodium, potassium, lithium, calcium ormagnesium, metal carbonates such as those of sodium, potassium, lithium,calcium or magnesium, metal bicarbonates such as sodium bicarbonate orpotassium bicarbonate, primary (I°), secondary (II°) or tertiary (III°)organic amines such as alkyl amines, arylalkyl amines, alkylarylalkylamines, heterocyclic amines or heteroaryl amines, ammonium hydroxides orquaternary ammonium hydroxides.

As non-limiting examples, such amines can include triethyl amine,trimethyl amine, diisopropyl amine, methyldiisopropyl amine,diazabicyclononane, tribenzyl amine, dimethylbenzyl amine, morpholine,N-methylmorpholine, N,N′-dimethylpiperazine, N-ethylpiperidine,1,1,5,5-tetramethylpiperidine, dimethylaminopyridine, pyridine,quinoline, tetramethylethylenediamine and the like. Non-limitingexamples of ammonium hydroxides, usually made from amines and water, caninclude ammonium hydroxide, triethyl ammonium hydroxide, trimethylammonium hydroxide, methyldiiospropyl ammonium hydroxide, tribenzylammonium hydroxide, dimethylbenzyl ammonium hydroxide, morpholiniumhydroxide, N-methylmorpholinium hydroxide, N,N′-dimethylpiperaziniumhydroxide, N-ethylpiperidinium hydroxide, and the like. As non-limitingexamples, quaternary ammonium hydroxides can include tetraethyl ammoniumhydroxide, tetramethyl ammonium hydroxide, dimethyldiiospropyl ammoniumhydroxide, benzylmethyldiisopropyl ammonium hydroxide,methyldiazabicyclononyl ammonium hydroxide, methyltribenzyl ammoniumhydroxide, N,N-dimethylmorpholinium hydroxide, N,N,N′,N′,-tetramethylpiperazenium hydroxide, and N-ethyl-N′-hexylpiperidiniumhydroxide and the like.

Metal hydrides, amide or alcoholates such as calcium hydride, sodiumhydride, potassium hydride, lithium hydride, sodium methoxide, potassiumtert-butoxide, calcium ethoxide, magnesium ethoxide, sodium amide,potassium diisopropyl amide and the like may also be suitable reagents.Organometallic deprotonating agents such as alkyl or aryl lithiumreagents such as methyl, phenyl or butyl lithium, Grignard reagents suchas methylmagnesium bromide or methymagnesium chloride, organocadiumreagents such as dimethylcadium and the like can also serve as bases forcausing salt formation or catalyzing the reaction. Quaternary ammoniumhydroxides or mixed salts are also useful for aiding phase transfercouplings or serving as phase transfer reagents.

The reaction media can comprise a single solvent, mixed solvents of thesame or different classes or serve as a reagent in a single or mixedsolvent system. The solvents can be protic, non-protic or dipolaraprotic. Non-limiting examples of protic solvents include water,methanol (MeOH), denatured or pure 95% or absolute ethanol, isopropanoland the like. Typical non-protic solvents include acetone,tetrahydrofurane (THF), dioxane, diethylether, tert-butylmethyl ether(TBME), aromatics such as xylene, toluene, or benzene, ethyl acetate,methyl acetate, butyl acetate, trichloroethane, methylene chloride,ethylenedichloride (EDC), hexane, heptane, isooctane, cyclohexane andthe like. Dipolar aprotic solvents include compounds such asdimethylformamide (DMF), dimethylacetamide (DMAc), acetonitrile,nitromethane, tetramethylurea, N-methylpyrrolidone and the like.

Non-limiting examples of reagents that can be used as solvents or aspart of a mixed solvent system include organic or inorganic mono- ormulti-protic acids or bases such as hydrochloric acid, phosphoric acid,sulfuric acid, acetic acid, formic acid, citric acid, succinic acid,triethylamine, morpholine, N-methylmorpholine, piperidine, pyrazine,piperazine, pyridine, potassium hydroxide, sodium hydroxide, alcohols oramines for making esters or amides or thiols for making the products ofthis invention and the like. Room temperature or less or moderatewarming (−10° C. to 60° C.) are the preferred temperatures of thereaction. If desired, the reaction temperature might be about −76° C. tothe reflux point of the reaction solvent or solvents.

An intermediate thioether can be oxidized to the sulfone in one stepusing two equivalents to oxidizing agent. Reagents for this process can,in a non-limiting example, include peroxymonosulfate (OXONE®), hydrogenperoxide, meta-chloroperbenzoic acid, perbenzoic acid, peracetic acid,perlactic acid, tert-butyl peroxide, tert-butyl hydroperoxide,tert-butyl hypochlorite, sodium hypochlorite, hypochlorus acid, sodiummeta-peroiodate, periodic acid and the like. Protic, non-protic, dipolaraprotic solvents, either pure or mixed, can be chosen, for example,methanol/water.

The oxidation can be carried out at temperature of about −78° to about50° degrees centigrade and normally selected from a range −10° C. toabout 40° C. Preparation of a desired sulfone can be carried out in atwo-step process using about one equivalent of oxidizing agent to firstform the sulfoxide at about 0° C. A second oxidation then pproduces thesulfone.

The solvents listed above can be used with these selective oxidationswith, for example, methanol or methanol/water being preferred along witha temperature of from about −10° C. to 30° C. It can be desirable in thecase of more active oxidizing agents, but not required, that thereactions be carried out under an inert gas atmosphere with or withoutdegassed solvents.

A hydroxamate can be prepared from the corresponding ester by reactionof the ester with one or more equivalents of hydroxylamine hydrochlorideat room temperature or above in a solvent or solvents such as thoselisted above. This exchange process can be further catalyzed by theaddition of additional acid.

Alternatively, a base such as a salt of an alcohol used as a solvent,for example, sodium methoxide in methanol, can be used to formhydroxylamine in situ which can exchange with an ester or amide. Theexchange can be carried out with a protected hydroxyl amine such astetrahydropyranylhydroxyamine (THPONH₂), benzylhydroxylamine (BnONH₂),and the like in which case compounds in which the ester is atetrahydropyranyl (THP) or benzyl (Bn) ester.

Removal of the protecting groups when desired, for example, followingfurther transformations in another part of the molecule or followingstorage, is accomplished by standard methods well known in the art suchas acid hydrolysis of the THP group or reductive removal of the benzylgroup with hydrogen and a metal catalyst such as palladium, platinum,palladium on carbon or nickel.

Oxidizable functional groups are readily recognized by those skilled inthe art and alternative synthesis can be used such as theprotection/deprotection sequence.

Acids can be converted into activated carbonyl compounds using reagentswell know in the art including the peptide and protein synthesis andamino acid coupling or conjugation art. Examples of such reagents arethionyl chloride, oxalyl chloride, phosphorus oxychloride, HOBT,isobutylchloroformate an the like. These valuable activated carbonylintermediates can then be transformed into hydroxamic acids orhydroxamic acid derivatives such as H, benzyl or THP. Preparation of orinterconversion between the hydroxylamine or hydroxylamine derivativecompounds or acids or amides or esters can be carried out by one skilledin the art using the methods discussed above or by other techniques.

The amine function in the intermediate compounds use a protecting groupto facilitate the transformations. Decisions involving the selection ofprotecting groups and their use can be made by a person skilled in theart. Especially useful are the techniques and reagents used in protein,peptide and amino acid coupling and transformation chemistry. The use ofthe tert-butoxycarbonyl (BOC), benzyloxycarbonyl (Z) and N,N-dibenzylgroups as will as their synthesis and removal are examples of suchprotection schemes.

Coupling of the amino acids, amino esters, amino acid hydroxamates orhydroxamate derivatives and amino acid amides of the precursor(intermediate) compounds with, for example, other amino acids, amines,alcohols, amides or acids is also carried out by methods well known inthe art such as, for example, active ester or mixed anhydride couplingswith preferred bases if required being moderate tertiary amines such asN-methylmorpholine. Removal of a preexisting group that can also serveas a protecting group or blocking group such as the acetyl group and thelike is also accomplished using standard hydrolysis conditions such asbase hydrolysis or exchange or acid exchange or hydrolysis.

In the case of compounds with an amine group, it is sometimes desirableto use acidic conditions with a reagent such as hydrogen peroxide and/orin combination with an acidic reagent such as periodic acid, peraceticacid and the like. It should also be noted by one skilled in the artthat hydrolysis or exchange of the acetyl group may or may not effecthydrolysis or exchange of a ester, amide or hydroxamate function.

Preparation of yet another class of compounds of this invention, thosecontaining the alpha-hydroxy carbonyl function, typically uses the SN₂class of reactions. A bimolecular nucleophilic displacement (SN₂)reaction is illustrated in a step wherein a halogen is displaced by athiol compound or the salt of a thiol compound. The thiol anion can bederived from a preformed salt or the salt can be formed in situ viaaddition of a base.

Preferred bases are those that are hindered such that competition withthiolate anion in a two stage reaction is minimized. The solvents,solvent mixtures or solvent/reagent mixtures discussed are satisfactorybut non-protic or dipolar aprotic solvents such as acetone,acetonitrile, DMF and the like are examples of a preferred class.

A protecting group P on the alpha-hydroxy group canalso be utilized.Such protecting groups can include acyl groups, carbamoyl groups,ethers, alkoxyalkyl ethers, cycloalkyloxy ethers, arylalkyl groupstrisubstituted silyl groups and the like. Examples of such protectinggroups include acetyl, THP, Benzyl, Z, tert-butyldimethylsilyl (TBDMS)groups. The preparation of such protected alcohols as well as theremoval of the protecting groups is well known in the art and itspractitioners.

The selection of an atmosphere for the reactions of these Schemes aswell as the other Schemes depends, as usual, a number of variables knownto those skilled in the art. The choices can be an inert atmosphere suchas nitrogen, argon, helium and the like or normal or dry air. Preferredis the use of an inert atmosphere if there is an uncertantity as to therequirements of the process.

One of these variables particularly requiring the attention of theskilled person is control of oxidation by air or another means of athiol or the salt of a thiol to its corresponding disulfide or mixeddisulfide. The used of a damp atmosphere while carrying out anorganometallic compound requiring synthesis not desirable for eithereconomic or safety reasons whereas the use of air is normal for aqueoushydrolysis or exchange reactions where oxidation, for example, is notprobable.

Addition of an organometallic reagent such as a Grignard Reagent,lithium organometallic reagent, zinc organometallic reagent, cadiumorganometallic reagent, sodium organometallic reagent or potassiumorganometallic regent to a carbonyl group such as an aldehyde, ketone,ester, amide (primaryI, secondary, tertiary), acid chloride, anhydride,mixed anhydride, hydroxamate derivative (mono- or bis-), carbonate,carbamate or carbon dioxide is illustrated in the Schemes such asSchemes A, B and C. The products of such reactions of organometalliccompounds with carbonyl compounds are well known to those skilled in theart. Well know examples include the preparation of alcohols by reactionwith aldehydes, acids by reaction with carbon dioxide and esters byreaction with carbonate esters.

For example, in Scheme A, the product of such a reaction can be analcohol such as compound 39 or an ester, amide, ketone or aldehyde. Itis also recognized by those skilled in the art that the carbonylcompound and the organometallic compound can be exchanged orinterchanged or otherwise manipulated to synthesize the same or asimilar compound. For example, although not contemplated herein,carbonyl compound 38 in Scheme A wherein R⁶ is methyl (or ethyl) can bereacted with ethyl magnesium bromide (or methyl magnesium bromide) toform compound 39 where R⁷ is ethyl (or methyl) and organometalliccompound 53 in Scheme B where one of R⁷ and R⁶ is methyl one is ethylcan be treated with water to also form compound 39.

An alcohol can also be converted into a halogen or sulfonate ester.Either product, as shown with the sulfides, can be oxidized or, onceoxidized, reduced back to a sulfide or sulfoxide. In addition, thealcohol with the sulfur oxidized can also be converted into, forexample, its corresponding halogen or sulfonated ester.

The halogen compounds such as those in Schemes A, B and C, for example,with or without the sulfur oxidized can be reacted with a metal to forman organometallic reagent such as those listed above. The organometalliccompound can then be reacted with a carbon-oxygen double bond-containingmolecule to produce precursors to compounds of this invention includinghomologous acids, esters, amides (primary, secondary, tertiary),ketones, aldehydes and the like.

If the product of the reaction of an organometallic compound with acarbonyl compound is itself another carbonyl containing compound such asshown, for example, by the synthesis of compounds 64 or 65 in Scheme C,the product can be either a metalloprotease inhibiting product of thisinvention or an intermediate for the synthesis of a homologousmetalloprotease inhibiting compound of this invention. As was discussedabove with respect to alcohols and illustrated in these Schemes, thesecarbonyl products can be oxidized at sulfur before or after furthermodification.

A lactone ring where R² through R⁷ inclusive are as defined above can beopened with a thiolate anion to provide a 4-thia acid (omega-thia acid,gamma-thia acid) or salt. An example of a preferred thiol is4-phenoxybenzenethiol. The sulfide formed can them be oxidized to thecorresponding sulfone, converted to the hydroxamate or protectedhydroxamate, deprotected if required all by methods discussed andillustrated above and known in the art.

Alternatively, a Lewis acid in the presence of a thiol can be used toform the thia acid. Opening of the lactone with a Lewis such as zincbromide or zinc chloride in the presence of thionyl bromide or thionylchloride can provide an omega-halo acid halide (activated carbonyl).This intermediate derivatives as desired at the carbonyl carbon can beprepared to provide a protected carbonyl compounds such as an ester oran amide or used to form a hydroxamic acid or protected hydroxamic aciddirectly; i.e., a omega-halo ester, amide, hydroxamic acid or protectedhydroxamate.

The 4-chloro or 4-bromo group can be displaced via a nucleophilicsubstitution reaction (SN₂) using a —SR¹ reagent to provide athia-compound that can then be oxidized as outlined above to provide adesired compound. Preferred lactones can include 2-methylbutyrolactone,2-hydroxy-3,3-dimethylbutyrolactone and 2-piperidylbutyrolactone.Preferred omega-haloesters include, methyl 2,2-dimehyl-4 chlorobutyrateand ethyl 4-bromobutyrate.

Alpha-halolactones can be utilized in the preparation of compounds ofthis invention wherein the alpha-carbon of the product hydroxamic acidsare substituted with a nucleophile such as a hydroxyl, ether, azide oran amine. These intermediates, when stable to the reaction conditions,properly protected or converted in a later step to the desired functioncan provide substrates for the lactone dependant reactions discussedabove. Bromobutyrolactone is a preferred halolactone.

Compounds of this invention can be prepared by alkylation of a carbanion(nucleophile) generated from a protected carboxylic acid using processesknown in the art. Protecting groups for the carboxyl function include,for example, esters such as tert-butyl esters. Bases for forming theanion are can be organometallic reagents such as tert-butyl lithium,metal amides such as lithium diisopopyl amide (LDA) or alkoxides such aspotassium tert-butoxide. Other candidate bases are discussed above.

Following or during formation of the anion, the alkylating agent(electrophile) is added which undergoes a nucleophilic substitutionreaction. Electrophilic substrates for displacement can include, forexample, dihalo alkanes such as 1,2-dihaloalkanes or mono-halo-monosulfated alkanes or bissulfonate alkane esters. 1,2-di-Bromoethanes,1-chloro-2, bromoethanes, 1-chloro-2-tosylethanes and1,2-di-toluenesulfonylethanes are examples of such bis-electrophiles.1-Bromo-2-chloro-ethane is a preferred electrophile.

Activated ester groups are well known in the art and can include, forexample, di-easters such as malonates, ester-ketones such as acetoaceticesters or ester-aldehydes that are subject to carbonyl additionreactions. Alkylation with one equivalent of alkyating agent followed byderivatization of the new omega carbonyl group with, for example, anorganometallic reagent or reduction to form an alcohol which can then bederivatized to form a carbon halogen bonds or an activated ester such asa sulfate ester. These omega-substituted compounds can serve assubstrates for the thioate displacement and oxidation reactionsdiscussed above to form the carboxylic acid compounds or intermediatesof this invention.

Omega-haloalcohols can be useful starting materials for the preparationof compounds of this invention using alternative synthetic sequencesfrom those discussed above. They can serve as substrates for R¹ thiolatedisplacement (SN₂) to provide 4-sulfides (thio ethers) which can then beoxidized to the desired sulfones. The HS-R¹ compounds can be prepared asdiscussed below and oxidized as discussed above. Preparation of the R¹group can be via an intermediate such as a fluorothiophenol followed bydisplacement of the fluoride with a second nucleophile to producecompounds or intermediates of this invention. Flourothiophenol andphenol and 2,3-dimethyl phenol are examples of preferred thiols andphenols, respectively. The sulfone alcohols can be oxidized to thecorresponding carboxylic acids as well as to the correspondingaldehydes.

The carboxylic acids or protected carboxylic acids can be utilized aspresented herein. The aldehydes can serve as useful intermediates forhomologation to an alpha-hydroxysulfone acid compound that can serve asa substrate for preparation of a hydroxamic acid or hydroxamate of thisinvention. Homologation of an aldehyde can be carried out by adding acyanide to the aldehyde to form a alpha-cyano-omegasulfone (cyanohydrin)which can then be hydrolysed with an acid such as those discussed aboveto form a alpha-hydroxy carboxylic acid useful in the synthesis ofcompounds of this invention. Cyanohydrins can be prepared by methodswell known in the art such as treatment of an aldehyde with a metalcyanide, hydrogen cyanide or trimethylsilylcyanide.Trimethylsilylcyanide is a preferred reagent.

The preparation of compounds of this invention based onalpha-oxygen-substituted compounds such as the hydroxyl group isdiscussed and illustrated and the methods are well known in the art.Protection of the alcohols of this invention or of the intermediatealcohols used in this invention is also well known.

The preparation of ethers can be carried out by forming a salt of thealcohol and treating this nucleophile with an electrophile such as ahalide or an activated ester such as a sulfate ester. The salt is formedby treating the alcohol with a base such as is discussed above. Examplesof such bases are lithium alkyls, metal hydrides or the metal salts ofan amine such as LDA.

Halides can be chlorides, bromides or iodides and sulfates can be, forexample, benzene sulfonates, tosylates, mesylates or triflates. Anexample of a preferred electrophile is 2-chloromethylpyridine and apreferred base is sodium hydride. Alternatively, the alcohol can beconverted into a leaving group (electrophilic reagent) and then treatedwith a nucleophile. Examples of such leaving groups include sulfateesters such tosylates, mesylates and triflates whose preparation isdiscussed above. The triflate is a preferred leaving group.

Displacement of these groups with nucleophiles is well known in the artand discussed and/or illustrated above. The nucleophiles can behydroxide to allow inversion of stereochemistry, alkoxides to formethers, amines or ammonia to form substituted amines or an azide anionto form an azide. A preferred nucleophile the is tetra-(n-butyl)ammoniumazide. The azido compound, for example, can be reduced to form the aminoacid. Reductions are discussed above and are well known in the art. Apreferred method is hydrogenation with palladium on carbon catalyst.

The amines, including the amino acids, of this invention can be acylatedor alkylated by methods well known in the art. The amides formed can beconsidered as protected amines or as end products of this invention.Acylation to form such derivatives as tert-butoxycarbonyl andcarbobenzyloxy carbonyl group is discussed above. Other acyl (Ac) groupscan be, for example, acetyl, haloacetyl, aroyl, substituted aroyl,heteroaroyl, substituted heteroaroyl or other groups as required. Theamines can be acylated using anhydrides, mixed anhydrides, acidchlorides or activated esters. Usually such acylations are carried outin presence of a base such as the bases discussed above and well knownin the art. Examples are N-methyl-morpholine, triethylamine and thelike.

The carboxyl compounds useful herein having amide substituents can betreated, converted or interconverted as shown and/or dicussed above toform the products of this invention. In addition, the haloacetylcompounds such as the preferred 2-chloroacetamide derivative can betreated with an amine as a nucleophile to yield an aminoacid. Again,these reactions are well known in the art. A preferred amine ismorpholine.

The cyclic amino acids used to prepare desired compounds can be preparedin ways know to those skilled in the art. Reduction of heteroaryl orunsaturated or partially unsaturated heterocycles can be carried out.For example, the six membered ring compounds can be synthesized byreduction of the corresponding 2-, 3- or 4-pyridine carboxylic acids,2-, or 3-pyrazole carboxylic acids or derivatives thereof. The reductioncan by hydrogenation in the presence of a catalyst or hydride reductionusing a hydride transfer agent such as lithium aluminum hydride. Thestarting amino acids or their derivatives, such as ethyl isonipecotate,ethyl nipecotate, pipecolinic acid, proline or its isomers,pyroglutamate or its isomers are starting materials that can be used toprepared a compound of this invention.

The R, S and RS isomers of the amino acids can be used. Some startingmaterial can be obtained from commercial sources. A preferred startingmaterial is ethyl isonipecotate.

Alkylation of the aminoacid at the carbon alpha to the carbonyl group toform a useful compound can be carried out by first forming an anionusing a base. Exemplary bases are discussed elsewhere. The preferredbases are strong bases that are either hindered and/or non-nucleophilicsuch as lithium amides, metal hydrides or lithium alkyls. A preferredbase is lithium diisopropylamide (LDA) in a dipolar aprotic solvent orTHF.

Following or during formation of the anion, an alkylating agent (anelectrophile) is added which undergoes a nucleophilic substitutionreaction. Non-limiting examples of such alkylating agents are1,2-dihaloalkanes or haloalkanes also substituted by an activated estergroup. Activated ester groups are well known in the art and can include,for example, an ester of a 2-halo-alcohol such as a bromo-, iodo- orchloro-ethane para-toluene sulfonate, triflate or mesylate. A preferredalkylating agents is 1-bromo-2-chloroethane.

The nitrogen substituent on the cyclic aminoacid portion of thecompounds of this invention can be varied. In addition, this can beaccomplished at different stages in the synthetic sequence based on theneeds and objectives of the skilled person preparing the compounds ofthis invention.

The N-side chain variations can include replacing the hydrogensubstituent with a alkyl, arylalkyl, alkene or alkyne. This can beaccomplished by methods well known in the art such as alkylation of theamine with an electrophile such as halo- or sulfate ester (activatedester) derivative of the desired sidechain. This can be done in thepresence of a base such as those discussed above and in a pure or mixedsolvent as discussed above. A preferred base is postassium carbonate anda preferred solvent is DMF.

The alkenes and alkynes can be reduced. if desired, by, for example,hydrogenation with a metal catalyst and hydrogen, to an alkyl orarylalkyl compound of this invention and the alkyne or arylalkyne can bereduced to a alkene of alkane with under catalytic hydrogenationconditions as discussed above dor with an deactivated metal catalyst.Catalysts can include, for example, Pd, Pd on Carbon, Pt, PtO₂ and thelike. Less robust catalysts include such thing as Pd on BaCO₃ or Pd withquinoline or/and sulfur.

An alternative method for alkylation of the amine nitrogen is reductivealkylation. This process, well known in the art, allows treatment of thesecondary amine with an aldehyde or ketone in the presence of a reducingagent such as borane, borane:THF, borane:pyridine, lithium aluminumhydride. Alternatively, reductive alkylation can be carried outhydrogenation conditions in the presence of a metal catalyst. Catalysts,hydrogen pressures and temperatures are discussed above and are wellknown in the art. A preferred reductive alkylation catalyst isborane:pyridine complex.

The compounds of this invention include compounds wherein thesubstituent on nitrogen of the cyclic amino acids as listed aboveprovide amino acid carbamates. Non-limiting examples of these carbamatesare the carbobenzoxycarbonyl (Z, CBZ, benzyloxycarbonyl),isobytoxycarbonyl and tert-butoxycarbonyl (BOC, t-BOC) compounds. Thesematerials can be made, as discussed above, at various stages in thesynthesis based on the needs and decisions made by a person skilled inthe art using methods well know in the art.

Useful synthetic techniques and reagents include those used in protein,peptide and amino acid synthesis, coupling and transformation chemistry.The use of the tert-butoxycarbonyl (BOC) and benzyloxycarbonyl (Z) aswill as their synthesis and removal are examples of such protection orsynthesis schemes discussed above. Transformations of amino acids, aminoesters, amino acid hydroxamates, amino acid hydroxamate derivatives andamino acid amides of this invention or compounds used in this inventioncan be carried out as discussed and/or illustrated above. This includes,for example, active ester or mixed anhydride couplings wherein preferredbases, if required, are tertiary amines such as N-methylmorpholine.

Reagents for protection of the amine group of the protected amino acidsinclude carbobenzoxy chloride, iso-butylchloroformate,tert-butoxycarbonyl chloride, di-tert-butyl dicarbonate and the likewhich are reacted with the amine in non-protic or dipolar aproticsolvents such as DMF or THF or mixtures of solvents. A preferred reagentis di-tert-butyl dicarbonate and a preferred solvent is THF. Furtherconversion of the cyclic amino acids of this invention includingalkylation, displacement with a thiol or thiolate, oxidation to asulfone, and conversion into a hydroxamic acid or hydroxamate derivativecan be carried out discussed herein.

Sulfone compounds such as those where R¹ is nitroaryl can be prepared ascompounds of this invention by synthesis of a thiol or thiolatenucleophile, displacement of an electrophile (X) by the nucleophilicthiol or thiolate and oxidation of the product thia ether (sulfide) tothe sulfone. For example, displacement of the electrophilic group X witha nitro-benzenethiol can yield a compound where R¹ is nitrobenzene thatcan be reduced to provide a useful amino compound wherein R¹ is ananiline. It should be noted that nitrobenzenethiol is an example and notto be considered as limiting or required. Oxidation of the thioetherproduct can be carried out as discussed below when desired.

The reduction of nitro groups to amines is will know in the art with apreferred method being hydrogenation. There is usually a metal catalystsuch as Rh, Pd, Pt, Ni or the like with or without an additional supportsuch as carbon, barium carbonate and the like. Solvents can be protic ornon-protic pure solvents or mixed solvents as required. The reductionscan be carried out at atmospheric pressure to a pressure of multipleatmospheres with atmospheric pressure to about 40 pounds per square inch(psi) preferred. The amino group can be alkylated if desired, oracylated with, for example, an aroyl chloride, heteroaryl chloride orother amine carbonyl forming agent to form an R¹ amide.

The amino sulfone or thioether can also be reacted with a carbonic acidester chloride, a sulfonyl chloride, a carbamoyl chloride or anisocyanate to produce the corresponding carbamate, sulfonamides, orurea. Acylation of amines of this type are well known in the art and thereagents are also well known.

Usually, these reactions are carried out in aprotic solvents under aninert or/and dry atmosphere at about 45° C. to about −10° C. Anequivalent of a non-competitive base is usually used with sulfonylchloride, acid chloride or carbonyl chloride reagents. Following orbefore this acylation step, synthesis of the hydroxamic acid products ofthis invention can proceed as discussed.

Other thiol reagents can also be used in the preparation of compounds ofthis invention. Examples are fluoroaryl, fluoroheteroaryl, azidoaryl orazidoheteroaryl or heteroaryl thiol reagents. These thiols can be used anucleophiles to as discused above. Oxidation to the correspondingsulfone can then be carried out. The fluoro substituted sulfone can betreated with a nucleophile such as ammonia, a primary amine, aquaternary ammonium or metal azide salt, under pressure if desired, toprovide an azido, amino or substituted amino group that can then bereacted an activated benzoic or substituted benzoic acid derivative toform a benzamide. Azides can be reduced to an amino group using, forexample, hydrogen with a metal catalyst or metal chelate catalyst or byan activated hydride transfer reagent. Hydrazo compounds can be oxidizedto azo compounds and axo compounds can be reduced to hydrazo compounds.The amines can be acylated as discussed above.

Preferred methods of preparing aminethiol intermediates of thisinvention include protection of an aromatic or heteroaromatic thiol withtrityl chloride to form the trityl thiol derivative, treatment of theamine with as reagent such as an aromatic or heteraromatic acid chlorideto form the amide, removal ot the trityl group, with acid to form thethiol. Preferred acylating agents include benzoyl chloride and preferredtrityl remoing reagents include triflouroacetic acid andtrisiopropylsilane.

The fluorine on fluorosulfone intermediates can also be displaced withother aryl or heteroaryl nucleophiles for form compounds of thisinvention. Examples of such nucleophiles include salts of phenols,thiophenols, —OH group containing aromatic heterocyclic compounds or —SHcontaining heteroaryl compounds.

Tautomers of such groups azo, hydrazo, —OH or —SH are specificallyincluded as useful isomers. A preferred method of preparingintermediates in the synthesis of the substituted sulfones is byoxidation of an appropriate acetophenone, prepared from aflouroacetophenone, with for example, peroxymonosulfate, to form thecorresponding phenol-ether. That phenol-ether is converted into itsdimethylthiocarbamoyl derivative using dimethylthiocarbamoyl chloride,followed by rearranging the dimethylthiocarbamoyl derivative with heatto provide the thiol required for preparation of the thioetherintermediate.

Salts of the compounds or intermediates of this invention are preparedin the normal fashion wherein acidic compounds are reacted with basessuch as those discussed above to produce metal or nitrogen containingcation salts. Basic compounds such as amines can be treated with an acidto for form the amine salt. A preferred amine salt is the hydrochloridesalt formed by reaction of the free base with HCl or hydrochloric acid.

Compounds of the present can possess one or more asymmetric carbon atomsand are thus capable of existing in the form of optical isomers as wellas in the form of racemic or nonracemic mixtures thereof. The opticalisomers can be obtained by resolution of the racemic mixtures accordingto conventional processes well known in the art, for example byformation of diastereoisomeric salts by treatment with an opticallyactive acid or base. Examples of appropriate acids are tartaric,diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric andcamphorsulfonic acid and then separation of the mixture ofdiastereoisomers by crystallization followed by liberation of theoptically active bases from these salts. A different process forseparation of optical isomers involves the use of a chiralchromatography column optimally chosen to maximize the separation of theenantiomers.

Still another available method involves synthesis of covalentdiastereoisomeric molecules, e.g., esters, amides, acetals, ketals, andthe like, by reacting compounds of Formula I with an optically activeacid in an activated form, a optically active diol or an opticallyactive isocyanate. The synthesized diastereoisomers can be separated byconventional means such as chromatography, distillation, crystallizationor sublimation, and then hydrolyzed to deliver the enantiomericaly purecompound. In some cases hydrolysis to the parent optically active drugis not necessary prior to dosing the patient because the compound canbehave as a prodrug. The optically active compounds of Formula I canlikewise be obtained by utilizing optically active starting materials.

In addition to the optical isomers or potentially optical isomersdiscussed above, other types of isomers are specifically intended to beincluded in this discussion and in this invention. Examples include cisisomers, trans isomers, E isomers, Z isomers, syn- isomers, anti-isomers, tautomers and the like. Aryl, heterocyclo or heteroaryltautomers, heteroatom isomers and ortho, meta or para substitutionisomers are also included as isomers. Solvates or solvent additioncompounds such as hydrates or alcoholates are also specifically includedboth as chemicals of this invention and in, for example, formulations orpharmaceutical compositions for delivery.

Treatment Process

A process for treating a host mammal having a condition associated withpathological matrix metalloprotease activity is also contemplated. Thatprocess comprises administering a compound described hereinbefore in anMMP enzyme-inhibiting effective amount to a mammalian host having such acondition. The use of administration repeated a plurality of times isparticularly contemplated.

A contemplated compound is used for treating a host mammal such as amouse, rat, rabbit, dog, horse, primate such as a monkey, chimpanzee orhuman that has a condition associated with pathological matrixmetalloprotease activity.

Also contemplated is the similar use of a contemplated compound in thetreatment of a disease state that can be affected by the activity ofmetalloproteases such as TNF-α convprtase. Exemplary of such diseasestates are the acute phase responses of shock and sepsis, coagulationresponses, hemorrhage and cardiovascular effects, fever andinflammation, anorexia and cachexia.

In treating a disease condition associated with pathological matrixmetalloproteinase activity, a contemplated MMP inhibitor compound can beused, where appropriate, in the form of an amine salt derived from aninorganic or organic acid. Exemplary acid salts include but are notlimited to the following: acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, mesylate andundecanoate.

Also, a basic nitrogen-containing group can be quaternized with suchagents as lower alkyl (C₁-C₆) halides, such as methyl, ethyl, propyl,and butyl chloride, bromides, and iodides; dialkyl sulfates likedimethyl, diethyl, dibuytl, and diamyl sulfates, long chain (C₈-C₂₀)halides such as decyl, lauryl, myristyl and dodecyl chlorides, bromidesand iodides, aralkyl halides like benzyl and phenethyl bromides, andothers to provide enhanced water-solubility. Water or oil-soluble ordispersible products are thereby obtained as desired. The salts areformed by combining the basic compounds with the desired acid.

Other compounds useful in this invention that are acids can also formsalts. Examples include salts with alkali metals or alkaline earthmetals, such as sodium, potassium, calcium or magnesium or with organicbases or basic quaternary ammonium salts.

In some cases, the salts can also be used as an aid in the isolation,purification or resolution of the compounds of this invention.

Total daily dose administered to a host mammal in single or divideddoses of an MMP enzyme-inhibiting effective amount can be in amounts,for example, of about 0.001 to about 100 mg/kg body weight daily,preferably about 0.001 to about 30 mg/kg body weight daily and moreusually about 0.01 to about 10 mg. Dosage unit compositions can containsuch amounts or submultiples thereof to make up the daily dose. Asuitable dose can be administered, in multiple sub-doses per day.Multiple doses per day can also increase the total daily dose, shouldsuch dosing be desired by the person prescribing the drug.

The dosage regimen for treating a disease condition with a compoundand/or composition of this invention is selected in accordance with avariety of factors, including the type, age, weight, sex, diet andmedical condition of the patient, the severity of the disease, the routeof administration, pharmacological considerations such as the activity,efficacy, pharmacokinetic and toxicology profiles of the particularcompound employed, whether a drug delivery system is utilized andwhether the compound is administered as part of a drug combination.Thus, the dosage regimen actually employed can vary widely and thereforecan deviate from the preferred dosage regimen set forth above.

A compound useful in the present invention can be formulated as apharmaceutical composition. Such a composition can then be administeredorally, parenterally, by inhalation spray, rectally, or topically indosage unit formulations containing conventional nontoxicpharmaceutically acceptable carriers, adjuvants, and vehicles asdesired. Topical administration can also involve the use of transdermaladministration such as transdermal patches or iontophoresis devices. Theterm parenteral as used herein includes subcutaneous injections,intravenous, intramuscular, intrasternal injection, or infusiontechniques. Formulation of drugs is discussed in, for example, Hoover,John E., Reminaton's Pharmaceutical Sciences, Mack Publishing Co.(Easton, Pennsylvania: 1975) and Liberman, H.A. and Lachman, L., Eds.,Pharmaceutical Dosage Forms, Marcel Decker, (New York, N.Y.: 1980).

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation can also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that can be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil can be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables. Dimethyl acetamide, surfactantsincluding ionic and non-ionic detergents, polyethylene glycols can beused. Mixtures of solvents and wetting agents such as those discussedabove are also useful.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable nonirritating excipient such as cocoabutter, synthetic mono- di- or triglycerides, fatty acids andpolyethylene glycols that are sold at ordinary temperatures but liquidat the rectal temperature and will therefore melt in the rectum andrelease the drug.

Solid dosage forms for oral administration can include capsules,tablets, pills, powders, and granules. In such solid dosage forms, thecompounds of this invention are ordinarily combined with one or moreadjuvants appropriate to the indicated route of administration. Ifadministered per os, the compounds can be admixed with lactose, sucrose,starch powder, cellulose esters of alkanoic acids, cellulose alkylesters, talc, stearic acid, magnesium stearate, magnesium oxide, sodiumand calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum,sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, andthen tableted or encapsulated for convenient administration. Suchcapsules or tablets can contain a controlled-release formulation as canbe provided in a dispersion of active compound in hydroxypropylmethylcellulose. In the case of capsules, tablets, and pills, the dosage formscan also comprise buffering agents such as sodium citrate, magnesium orcalcium carbonate or bicarbonate. Tablets and pills can additionally beprepared with enteric coatings.

For therapeutic purposes, formulations for parenteral administration canbe in the form of aqueous or non-aqueous isotonic sterile injectionsolutions or suspensions. These solutions and suspensions can beprepared from sterile powders or granules having one or more of thecarriers or diluents mentioned for use in the formulations for oraladministration. The compounds can be dissolved in water, polyethyleneglycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil,sesame oil, benzyl alcohol, sodium chloride, and/or various buffers.Other adjuvants and modes of administration are well and widely known inthe pharmaceutical art.

Liquid dosage forms for oral administration can include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions can also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring, andperfuming agents.

The amount of active ingredient that can be combined with the carriermaterials to produce a single dosage form varies depending upon themammalian host treated and the particular mode of administration.

BEST MODE FOR CARRYING OUT THE INVENTION

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limiting ofthe remainder of the disclosure in any way whatsoever.

EXAMPLE 1(S)-N,2-Dihydroxy-3,3-dimethyl-4-[(phenoxyphenyl)sulfonyl]butanamide

Part A: To a solution of 4-(phenoxy)benzenethiol (13.3 g, 65.8 mmol) inDMF (100 mL) was added K₂CO₃ (9.1 g, 65.8 mmol). To this solution wasadded S-pantolactone (8.5 g, 65.3 mmol) and the solution was heated toone hundred degrees Celsius for 4 hours. The solution was concentratedin vacuo and the residue was partitioned between ethyl acetate and 1NHCl. The organic layer was washed with saturated NaCl and dried overMgSO₄. To a solution of the crude sulfide in methanol (200 mL) and H₂O(50 mL) was added Oxone® (121 g) and the mixture stirred for 18 hours.The mixture was filtered and the filtrate was partitioned between ethylacetate and H₂O. The organic layer was dried over MgSO₄. A solution ofthe crude sulfone in methanol was treated with thionyl chloride (4.8 mL,65.8 mmol) and the solution was heated to reflux for 1 hour.Concentration in vacuo provided the methyl ester sulfone as a whitesolid (13.0 g, 53%).

Part B: To a solution of the methyl ester sulfone of part A (780 mg,2.06 mmol) in THF (10 mL) and methanol (10 mL) was added 50% aqueousNH₂OH (2.4 mL, 41.2 mmol). The solution stirred for 3 days and thenconcentrated in vacuo. Reverse phase chromatography (on silica,acetonitrile/H₂O) provided the title compound as a white solid (300 mg,38%) HPLC purity: 98.8%. MS(CI) MH⁺ calculated for C₁₈H₂₁NO₆S: 380,found 380.

EXAMPLE 2(R)-N,2-Dihydroxy-3,3-dimethyl-4-[(4-phenoxyphenyl)sulfonyl]butanamide

Part A: To a solution of 4-(phenoxy)benzenethiol (9.8 g, 48.5 mmol) inDMF was added K₂CO₃ (6.7 g, 48.5 mmol) followed by R-pantolactone (6.3g, 48.4 mmol). The solution was heated to one hundred degrees Celsiusfor 3 hours followed by concentration in vacuo. The residue waspartitioned between ethyl acetate and 1N HCl. The organic layer wasdried over MgSO₄ and concentrated in vacuo. To a solution of the crudesulfide in methanol (200 mL) and H₂O (50 mL) was added Oxone® (90 g, 145mmol) and the solution was stirred for 18 hours. The mixture wasfiltered and the filtrate was concentrated and partitioned between ethylacetate and H₂O. The organic layer was concentrated and dried overMgSO₄. After concentration in vacuo the residue was dissolved inmethanol and treated with thionyl chloride (3.54 mL, 48.5 mmol). Thesolution was heated to reflux for 1 hour. Concentration in vacuoprovided the methyl ester sulfone as a white solid (8.45 g, 54%).

Part B: To a solution of the methyl ester sulfone of part A (460 mg, 1.2mmol) in THF (5 mL) and methanol (5 mL) was added 50% aqueous NH₂OH (1mL). The solution stirred for 4 days at ambient temperature and 3 daysat fifty degrees Celsius. Concentration in vacuo followed by reversephase chromatography (on silica, acetonitrile/H₂O) provided the titlecompound as a white solid (95 mg, 21%). MS(CI) MH⁺ calculated forC₁₈H₂₁NO₆S: 380, found 380.

EXAMPLE 3 2,2-Dimethyl-N-hydroxy-4-[(4-phenoxyphenyl)sulfonyl]butanamide

Part A: To a solution of diisopropylamine (2.24 mL, 16 mmol) intetrahydrofuran (15 mL) cooled to zero degrees Celsius was addedn-butyllithium (1.6 M in hexanes, 10 mL) over 2 minutes. The solutionwas cooled to minus seventy-eight degrees Celsius and methyl isobutyrate(1.60 mL, 14 mmol) was added. After 30 minutes 1-bromo-2-chloroethane(1.3 mL, 16 mmol) was added. The cooling bath was removed and themixture was allowed to stir at ambient temperature for 2.5 hours. Thesolution was concentrated, diluted with 1N HCl and extracted withchloroform. The organic layer was dried over MgSO₄ and filtered throughsilica. Concentration in vacuo provided the crude chloride compound as avolatile oil (431 mg, 19%) and was used without further purification.

Part B: To a solution of sodium hydride (60% dispersion in mineral oil,104 mg, 2.6 mmol) in acetonitrile (10 mL) cooled to zero degrees Celsiuswas added 4-(phenoxy)benzenethiol (0.53 g, 2.6 mmol). After the solutionwas stirred for 10 minutes, the chloride compound of part A (431 mg, 2.6mmol) was added. The bath was removed and the reaction mixture wasstirred overnight at ambient temperature. Concentration in vacuofollowed by chromatography provided the sulfide as an oil (474 mg, 54%).

Part C: To a solution of the sulfide of part B (474 mg, 1.4 mmol)inglacial acetic acid (5 mL) was added 30% hydrogen peroxide (0.6 mL, 6mmol) and the mixture was heated over a steam bath for 40 minutes.Lyophilization followed by chromatography (hexane/ethyl acetate)provided the sulfone as an oil (469 mg, 90%).

Part D: To a solution of the sulfone of part A (460 mg, 1.3 mmol) in 95%ethanol (5 mL) was added KOH (150 mg) and the solution was warmed toreflux. After 1.5 hours, the reaction was cooled to ambient temperatureand adjusted to pH 4-5 using conc. HCl. The mixture was diluted withacetonitrile, then concentrated to dryness. The resulting acid wasdiluted with acetonitrile (4 mL) and O-tetrahydropyranyl hydroxylamine(176 mg, 1.5 mmol) was added, followed by1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.288 g,1.5 mmol). The mixture was stirred overnight, then diluted with waterand extracted with chloroform. The organic layer was dried over MgSO₄and concentrated in vacuo. Chromatography provided the ester as an oil(421 mg, 73%).

Part E: To a solution of the ester of part D (421 mg, 0.95 mmol) inmethanol (10 mL) was added toluenesulfonic acid (56 mg) and the solutionwas stirred 90 minutes at ambient temperature. Concentration in vacuofollowed by chromatography (on silica, chloroform/methanol/ammoniumhydroxide) provided the title compound as a white glass (237 mg, 69%).Analytical calculation for C₁₈H₂₁NO₅S·H₂O: C, 56.68; H, 6.08; N, 3.67.Found: C, 56.34; H, 5.52; N, 3.61.

EXAMPLE 4 N,2-Dihydroxy-4-[(4-phenoxyphenyl)-sulfonyl]butanamide

Part A: To a solution of 4-fluorothiophenol (10.0 g, 78.02 mmol) and3-chloro-1-propanol (7.2 mL, 85.82 mmol) in DMF (80 mL) was added K₂CO₃(32.4 g, 234.06 mmol). The solution stirred for 2 hours at ambienttemperature. After concentration in vacuo the residue was partitionedbetween ethyl acetate and H₂O and the organic layer was washed withsaturated NaCl and dried over MgSO₄. Concentration in vacuo provided acolorless oil. To a solution of the oil in methanol (300 mL) and H₂O (60mL) was added Oxone(D. The solution stirred for 2 hours. Afterfiltration to remove excess Oxone® the filtrate was concentrated invacuo and the residue was dissolved into H₂O and extracted with ethylacetate. The combined organic layers were washed with saturated NaHCO₃and saturated NaCl and dried over MgSO₄.

Concentration in vacuo provided the sulfone as a colorless oil (15.7 g,92%).

Part B: To a solution of the sulfone of part A (12.7 g, 58.2 mmol) andphenol (16.4 g, 174.6 mmol) in DMF (100 mL) was added K₂CO₃ (24.1 g,174.6 mmol) and the slurry stirred at one hundred degrees Celsius for 18hours. The slurry was concentrated in vacuo and the residue waspartitioned between ethyl acetate and H₂O. The organic layer was washedwith 1N HCl, saturated NaHCO₃ and saturated NaCl, and dried over MgSO₄.Chromatography (on silica, ethyl acetate/hexane) provided the phenoxycompound as a pinkish solid (12.3 g, 72%).

Part C: To a solution of the phenoxy of part B (13.0 g, 44.5 mmol) indichloromethane (60 mL) cooled to zero degrees Celsius, was addedtriethylamine (25 mL, 18.0 mmol). To this solution was added a solutionof SO₃·pyridine (28.3 g, 177.9 mmol) in DMSO (60 mL) dropwise. Thesolution stirred for 2 hours at zero degrees Celsius. The solution wasquenched in ice and extracted with ethyl acetate. The organic layer waswashed with 5% KHSO₄ and saturated NaCl and dried over MgSO₄.Concentration in vacuo provided the aldehyde as a tan solid (12.7 g,98%).

Part D: To a solution of the aldehyde of part C (12.9 g, 44.43 mmol) indichloromethane (150 mL) cooled to zero degrees Celsius was addedtrimethylsilyl cyanide (6.6 g, 66.65 mmol) and zinc bromide (15.0 g,66.65 mmol). The solution was stirred for 3 hours. The mixture wasconcentrated in vacuo and partitioned between ethyl acetate and 2N HCl.The organic layer was washed with saturated NaHCO₃ and saturated NaCland dried over MgSO₄. Chromatography (on silica, ethyl acetate/CH₂Cl₂)provided the cyano compound as a white solid (10.3 g, 73%).

Part E: To a solution of the cyano compound of part D (10.3 g, 32.3mmol) in glacial acetic acid (30 mL) was added 6N HC₁ (100 mL). Thesolution heated at ninety degrees Celsius for 2 hours. The solution wasconcentrated in vacuo to dryness to provide the acid as a tan solid (9.1g, 71%).

Part F: To a solution of the acid of part E (2.0 g, 5.9 mmol) andN-hydroxybenzotriazole (1.0 g, 7.14 mmol) in DMF was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.3 g, 6.54mmol). After 1 hour of stirring at ambient temperature 50% aqueous NH₂OH(1.1 mL, 17.8 mmol) and 4-methylmorpholine (2.0 mL, 17.8 mmol) wereadded. The solution was stirred for 1 hour. The solution wasconcentrated in vacuo and partitioned between ethyl acetate and 1N HCland the organic layer was washed with saturated NaHCO₃ and saturatedNaCl and dried over Na₂SO₄. Reverse phase chromatography (on silica,acetonitrile/H₂O) provided the title compound as a white solid (100 mg,5%). MS(CI) MH⁺ calculated for C₁₆H₁₇NO₆S: 352, found 352.

EXAMPLE 5 N-Hydroxy-2-methyl-4-[(4-phenoxyphenyl)sulfonyl]butanamide

Part A: To a solution of NaH (60% suspension in mineral oil, 0.88 g, 22mmol) in THF (20 mL) cooled to zero degrees Celsius was added4-(phenoxy)benzenethiol (4.04 g, 20 mmol). After 10 minutes, ethanol (5mL) was added, followed by α-methyl-γ-butyrolactone (2.38 g, 25 mmol),and the reaction mixture was warmed to reflux. After 20 hours, themixture was cooled and concentrated. The residue was diluted with waterand acidified with concentrated HCl. The aqueous mixture was extractedwith chloroform and the organic layer was dried over MgSO₄ andconcentrated in vacuo. Chromatography (on silica, hexane/ethyl acetate)provided the sulfide as an oil (3.74 g, 62%). MS(CI) MH⁺ calculated forC₁₇H₁₈O₃S: 303, found: 303.

Part B: To a solution of the sulfide of part A (3.74 g, 12.4 mmol) inglacial acetic acid (25 mL) was added 30% hydrogen peroxide (4.8 mL, 48mmol). The solution was heated over a steam bath for 40 minutes.Lyophilization followed by chromatography provided the sulfone as a wax(3.62 g, 89%).

Part C: To a solution of the sulfone of part B (2.40 g, 7.2 mmol) inacetonitrile (10 mL) was added O-tetrahydropyranyl hydroxylamine (0.90g, 7.7 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (1.48 g, 7.7 mmol). The mixture was stirred overnight,then diluted with water and extracted with chloroform. The organic layerwas dried over MgSO₄ and concentrated in vacuo. Chromatography providedthe ester as an oil (2.23 g, 71% yield).

Part D: To the ester of part C (2.23 g, 5.11 mmol) in methanol (60 mL)was added p-toluenesulfonic acid (1.2 g) and the solution was stirred 40minutes. Following neutralization with concentrated ammonium hydroxide,chromatography (on silica, chloroform/methanol/ammonium hydroxide)provided the title compound as a white wax (981 mg, 54%). Analyticalcalculation for C₁₇H₁₉NO₅S·0.5H₂O: C, 56.97; H, 5.62; N, 3.91. Found: C,56.90; H, 5.22; N, 4.02.

EXAMPLE 6 N-Hydroxy-4-[(4-methoxyphenyl)-sulfonyl]butanamide

Part A: To a solution of 4-methoxybenzenethiol (2.5 g, 17.83 mmol) andethyl 4-bromobutyrate (3.5 g, 17.83 mmol) in ethanol (50 mL) was cooledon an ice bath and triethylamine (2.73 mL, 19.61 mmol) was added. Thesolution stirred for 6 hours at ambient temperature. To this solutionwas added H₂O (10 mL) and Oxone® (22 g, 35.7 mmol) and the solutionstirred for 20 hours. The solution was filtered to remove excess Oxone®and the filtrate was concentrated in vacuo. The residue was dissolvedinto H₂O and extracted with ethyl acetate. The combined organic layerswere washed with saturated NaHCO₃ and saturated NaCl and dried overMgSO₄. Chromatography (on silica, ethyl acetate/hexane) provided thesulfone as a white solid (2.41 g, 47%). HPLC purity: 97%.

Part B: To a solution of the sulfone of part A (2.41 g, 8.42 mmol) andhydroxylamine hydrochloride (700 mg, 10.10 mmol) in methanol (50 mL),cooled to zero degrees Celsius, was added Na metal (470 mg, 20.20 mmol).After stirring at ambient temperature for 2 hours, the reaction wasquenched by the addition of dry ice to pH=7. Following concentration invacuo the residue was dissolved into H₂O and acidified to pH=3 with 2NHCl . The solution was extracted with ethyl acetate and the combinedorganic layers were washed with saturated NaCl and dried over Na₂SO₄.Chromatography (on silica, ethyl acetate/hexane) provided the titlecompound as a white solid (300 mg, 13%). HPLC purity: 98.7%. HRMScalculated for C₁₁H₁₅NO₅S: 274.0749, found 274.0779.

EXAMPLE 7 (+/−)-4-[[4-(3,4-Dimethylphenoxy)phenyl]-sulfonyl]-N,2-dihydroxybutanamide

Part A: To a solution of 4-fluorothiophenol (20 g, 156 mmol) in DMF (100mL) was added 3-chloro-1-propanol (11.5 g, 121 mmol) and K₂CO₃ (64.7 g,468 mmol) and the mixture was stirred for 18 hours. The solution wasremoved by concentration in vacuo and the residue was partitionedbetween ethyl acetate and H₂O. The organic layer was extracted 3 timeswith ethyl acetate and the combined organics were washed with saturatedNaCl and dried over Na₂SO₄. Concentration in vacuo provided the sulfideas an amber oil (30.53 g).

Part B: To a solution of the sulfide of part A (30.5 g) in methanol (450mL) and H₂O (50 mL) was added Oxone® (262 g, 426 mmol) and the mixturewas stirred for 18 hours. The mixture is filtered to collect the excesssolids and the filtrate was concentrated in vacuo. The residue waspartitioned between ethyl acetate and H₂O and the organic layer waswashed with 5% NaHCO₃ and saturated NaCl and dried over Na₂SO₄.Concentration in vacuo provided the sulfone as an amber oil (22.04 g,83%, 2 steps).

Part C: To a solution of the sulfone of part B (22.04 g, 101 mmol) inDMF (50 mL). To this solution is added 3,4-dimethylphenol (18.62 g, 152mmol) in DMF (50 mL) followed by K₂CO₃ (43.13 g, 312 mmol) and thesolution was heated at one hundred ten degrees Celsius for 17 hours. Thesolution was partitioned between ethyl acetate and H₂O and the organiclayer was washed with 1N HCl, 5% NaHCO₃, and NaCl and dried over Na₂SO₄.Chromatography (on silica, ethyl acetate/hexane) provided thedimethylphenoxyphenol as a white solid (15.17 g, 47%).

Part D: To a solution of dimethylphenoxyphenol of part C (15.17 g, 47.4mmol) in dichloromethane (80 mL) was added triethylamine (20 mL)followed by pyridine·SO₃ (22.46 g, 141 mmol) in DMSO (80 mL) addeddropwise. The solution was stirred for 1 hour. The reaction was quenchedby the addition of crushed ice and concentrated in vacuo to remove thesolvent. The solution was extracted with ethyl acetate and the organiclayer was washed with saturated NaCl and dried over MgSO₄. Concentrationin vacuo provided the aldehyde as an orange oil (15.03 g).

Part E: To a solution of the aldehyde of part D (15.6 g) indichloromethane (100 mL) was added trimethylsilyl cyanide (7.3 mL, 71.1mmol) followed by zinc iodide (2.27 g, 7.1 mmol) and the solution wasstirred on an ice bath for 17 hours. The solution is partitioned betweenethyl acetate and 2M HCl . The organic layer was washed with H₂O andsaturated NaCl and dried over MgSO₄. Filtration through a silica padprovided the nitrile as an amber oil (14.13 g).

Part F: A solution of the nitrile of part E (14.13 g) in glacial aceticacid (50 mL) and concentrated HCl (50 mL) was heated to one hundred tendegrees Celsius for 2 hours and was stirred for 18 hours. The solutionwas concentrated in vacuo to provide the acid as a brown oil (13.53 g,75%, three steps).

Part G: To a solution of the acid of part F (13.5 g, 35.7 mmol) inmethanol (100 mL) cooled to zero degrees Celsiius was added thionylchloride (4.1 mL, 56.2 mmol) dropwise and the solution is stirred atambient temperature for 72 hours. The solution was concentration invacuo and the residue was dissolved into ethyl acetate and washed with5% NaHCO₃ and saturated NaCl and dried over Na₂SO₄. Chromatography (onsilica, ethyl acetate/hexane) provided the methyl ester as a white solid(14.51 g, quantitative yield).

Part H: To a solution of the methyl ester of part G (630 mg, 1.6 mmol)in THF (30 mL) was added 50% aqueous hydroxylamine (1 mL) and thesolution was stirred for 140 hours. The solution is concentrated and theresidue was dissolved into ethyl acetate and washed with 5% NaHCO₃ anddried over Na₂SO₄. Concentration in vacuo provided the title compound asa white solid (450 mg, 69%). MS(CI) MH⁺ calculated for C₁₈H₂₁NO₆S: 380,found 380.

EXAMPLE 8(S)-N-Hydroxy-3,3-dimethyl-4-[(4-phenoxyphenyl)sulfonyl]-2-(3-pyridinylmethoxy)butanamideMonohydrochloride

Part A: To a solution of 4-(phenoxy)benzenethiol (13.3 g, 65.8 mmol) inDMF (100 mL) was added K₂CO₃ (9.1 g, 65.8 mmol). To this solution wasadded S-pantolactone (8.5 g, 65.3 mmol) and the solution was heated toone hundred degrees Celsius for 4 hours. The solution was concentratedin vacuo and the residue was partitioned between ethyl acetate and 1NHCl. The organic layer was washed with saturated NaCl and dried overMgSO₄. To a solution of the crude sulfide in methanol (200 mL) and H₂O(50 mL) was added Oxone® (121 g) and the mixture stirred for 18 hours.The mixture was filtered and the filtrate was partitioned between ethylacetate and H₂O. The organic layer was dried over MgSO₄. A solution ofthe crude sulfone in methanol was treated with thionyl chloride (4.8 mL,65.8 mmol) and the solution was heated to reflux for 1 hour.Concentration in vacuo provided the methyl ester sulfone as a whitesolid (13.0 g, 53%).

Part B: To DMF (12 mL) was added NaH (60% suspension in mineral oil, 255mg, 10.6 mmol) followed by the methy ester sulfone of part A (2.00 g,5.28 mmol). To a solution of 3-picolyl chloride hydrochloride (868 mg,5.28 mmol) in DMF (12 mL) was added NaH (60% suspension in mineral oil,257 mg, 10.7 mmol). After 5 minutes the solution of the sulfone wasadded to this solution of the chloride and the mixture stirred for 18hours at ambient temperature. The reaction was quenched by the additionof H₂O and the solution was concentrated in vacuo. The residue wasdissolved into ethyl acetate and H₂O and the aqueous is extracted twicewith ethyl acetate. The combined organic layers are washed withsaturated NaHCO₃ and saturated NaCl and dried over Na₂SO₄.Chromatography (on silica, ethyl acetate/hexane) provided the ether as asolid (950 mg, 38%).

Part C: To a solution of the ether of part B (950 mg, 2.0 mmol) inglacial acetic acid (15 mL) was added concentrated HCl (15 mL) and thesolution was heated to reflux for 3 hours. The solution was concentratedin vacuo provided the acid as a white foam (1.05 g, quantitative yield).

Part D: To a solution of the acid of part C (1.03 g, 2.0 mmol) in DMF(10 mL) was added N-hydroxybenzotriazole (301 mg, 2.2 mmol),4-methylmorpholine (1.02 mL, 10 mmol), O-tetrahydropyranyl hydroxylamine(725 g, 6.2 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride(500 mg, 2.6 mmol). The solution was stirred for 20 hoursat ambient temperature. The solution was partitioned between ethylacetate and H₂O and the organic layer was washed with saturated NaCl anddried over Na₂SO₄. Chromatography (on silica, ethyl acetate/hexane)provided the ester as a white solid (890 mg, 82%).

Part E: To a solution of the ester of part D (890 mg, 1.6 mmol) in 4MHCl in dioxane (5 mL) was added methanol (12 drops) and the solution wasstirred for 30 minutes. The solution was concentrated in vacuo andreverse phase chromatography (on silica, acetonitrile/H₂O) provided thetitle compound as a white solid (540 mg, 66%). MS(CI) MH⁺ calculated forC₂₄H₂₆N₂O₆S: 471, found 471.

EXAMPLE 8a Preparation of(S)-N-Hydroxy-3,3-dimethyl-4-[(4-phenoxyphenyl)sulfonyl]-2-(3-pyridinylmethoxy)butanamide

A solution of the HCl salt of example 8 in saturated NaHCO₃ wasextracted with ethyl acetate. The organic layer was washed withsaturated NaCl and dried over Na₂SO₄. Concentration in vacua providedthe title compound.

EXAMPLE 9 (S) -N-Hydroxy-3,3-dimethyl-4-[(4-phenoxyphenyl) sulfonyl]-2-(4-pyridinyl-methozy)butanamide Monohydrochloride

Part A: To a solution of 4-(phenoxy)benzenethiol (13.3 g, 65.8 mmol) inDMF (100 mL) was added K₂CO₃ (9.1 g, 65.8 mmol). To this solution wasadded S-pantolactone (8.5 g, 65.3 mmol) and the solution was heated to100° C. for 4 hours. The solution was concentrated in vacuo and theresidue was partitioned between ethyl acetate and 1N HCl . The organiclayer was washed with saturated NaCl and dried over MgSO₄. To a solutionof the crude sulfide in methanol (200 mL) and H₂O (50 mL) was addedOxone® (121 g) and the mixture stirred for 18 hours. The mixture wasfiltered and the filtrate was partitioned between ethyl acetate and H₂O.The organic layer was dried over MgSO₄. A solution of the crude sulfonein methanol was treated with thionyl chloride (4.8 mL, 65.8 mmol) andthe solution was heated to reflux for 1 hour. Concentration in vacuoprovided the methyl ester sulfone as a white solid (13.0 g, 53%).

Part B: To DMF (12 mL) was added NaH (60% suspension in mineral oil, 253mg, 10.6 mmol) followed by the methyl ester sulfone of part A (2.00 g,5.28 mmol). To a solution of 4-picolyl chloride hydrochloride (868 mg,5.28 mmol) in DMF (12 mL) was added NaH (60% suspension in mineral oil,255 mg, 10.7 mmol). After 5 minutes the solution of the sulfone wasadded to this solution of the chloride and the mixture stirred for 18hours at ambient temperature. The reaction was quenched by the additionof H₂O and the solution was concentrated in vacuo. The residue wasdissolved into ethyl acetate and H₂O and the aqueous was extracted twicewith ethyl acetate. The combined organic layers were washed withsaturated NaHCO₃ and saturated NaCl and dried over Na₂SO₄.Chromatography (on silica, ethyl acetate/hexane) provided the ether as asolid (1.07 mg, 43%).

Part C: To a solution of the ether of part B (1.07 mg, 2.15 mmol) inglacial acetic acid (15 mL) was added concentrated HCl (15 mL) and thesolution was heated to reflux for 3 hours. The solution was concentratedin vacuo provided the acid as a white foam (1.09 mg, quantitativeyield).

Part D: To a solution of the acid of part C (1.09 g, 2.0 mmol) in DMF(10 mL) was added N-hydroxybenzotriazole (301 mg, 2.2 mmol),4-methylmorpholine (1.02 mL, 10 mmol), O-tetrahydropyranyl hydroxylamine(725 g, 6.2 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (500 mg, 2.6 mmol). The solution stirred for 20 hours atambient temperature. The solution was partitioned between ethyl acetateand H₂O and the organic layer was washed with saturated NaCl and driedover Na₂SO₄. Chromatography (on silica, ethyl acetate/hexane) providedthe ester as a white solid (840 mg, 77%).

Part E: To a solution of the ester of part D (840 mg, 1.5 mmol) in 4MHCl in dioxane (5 mL) was added methanol (12 drops) and the solution wasstirred for 30 minutes. The solution was concentrated in vacuo andreverse phase chromatography (on silica, acetonitrile/H₂O) provided thetitle compound as a white solid (350 mg, 45%). MS(CI) MH⁺ calculated forC₂₄H₂₆N₂O₆S: 471, found 471.

EXAMPLE 9a(S)-N-Hydroxy-3,3-dimethyl-4-[(4-phenoxyphenyl)sulfonyl]-2-(4-pyridinylmethoxy)butanamide

A solution of the HCl salt of example 9 in saturated NaHCO₃ wasextracted with ethyl acetate. The organic layer was washed withsaturated NaCl and dried over Na₂SO₄. Concentration in vacuc providedthe title compound.

EXAMPLE 10 (S)-N-Hydroxy-3,3-dimethyl-4-[(4-phenoxyphenyl)sulfonyl]-2(2-pyridinyl methoxy)butanamide Monohydrochloride

Part A: To a solution of 4-(phenoxy)benzenethiol (13.3 g, 65.8 mmol) inDMF (100 mL) was added K₂CO₃ (9.1 g, 65.8 mmol). To this solution wasadded S-pantolactone (8.5 g, 65.3 mmol) and the solution was heated toone hundred degrees Celsius for 4 hours. The solution was concentratedin vacuo and the residue was partitioned between ethyl acetate and 1NHCl. The organic layer was washed with saturated NaCl and dried overMgSO₄. To a solution of the crude sulfide in methanol (200 mL) and H₂O(50 mL) was added Oxone® (121 g) and the mixture stirred for 18 hours.The mixture was filtered and the filtrate was partitioned between ethylacetate and H₂O. The organic layer was dried over MgSO₄. A solution ofthe crude sulfone in methanol was treated with thionyl chloride (4.8 mL,65.8 mmol) and the solution was heated to reflux for 1 hour.Concentration in vacuo provided the methyl ester sulfone as a whitesolid (13.0 g, 53%).

Part B: To a solution of the methyl ester sulfone (21.1 g, 57.8 mmol) inmethanol (120 mL) was added thionyl chloride (5.1 mL, 69.5 mmol) and thesolution was heated to reflux for 1 hour. The solution was concentratedand the residue was dissolved into ethyl acetate and washed withsaturated NaHCO₃, H₂O, and saturated NaCl and dried over Na₂SO₄.Chromatography (on silica, ethyl acetate/hexane) provided the methylester as a solid (13.3 g, 61%).

Part C: To a slurry of NaH (60% suspension in mineral oil, 253 mg, 6.32mmol) in DMF (12 mL) was slowly added the alcohol of part B (2.0 g, 5.28mmol) and the mixture was stirred for 30 minutes. To a slurry of NaH(60% suspension in mineral oil, 253 mg, 6.32 mmol) in DMF (12 mL) wasadded 2-picoyl chloride hydrochloride (868 mg, 5.28 mmol). This solutionwas added to the first mixture dropwise and the solution was stirred for18 hours. The reaction was quenched with H₂O and the solvent was removedby concentration in vacuo. The residue was partitioned between ethylacetate and H₂O. The organic layer was washed with saturated NaHCO₃ andsaturated NaCl and dried over Na₂SO₄. Chromatography (on silica, methylacetate/hexane) provided the ether as an oil (1.32 g, 53%).

Part D: A solution of the ether of part C (1.0 g, 2.0 mmol) in aceticacid (15 mL) and concentrated HCl (15 mL) was heated to reflux for 3.5hours. The solution was concentrated in vacuo to provide the acid as anoff-white foam (910 mg, 92%).

Part E: To a solution of the acid of part D (910 mg, 1.86 mmol) in DMF(10 mL) was added N-hydroxybenzotriazole (301 mg, 2.23 mmol),4-methylmorpholine (1.02 mL, 9.3 mmol), O-tetrahydropyranylhydroxylamine (675 mg, 5.7 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (499 mg,2.60 mmol) and the solution was stirred at ambient temperature for 18hours. The solution was concentrated in vacuo and the residue waspartitioned between ethyl acetate and H₂O. The organic layer was washedwith H₂O and saturated NaCl and dried over Na₂SO₄. Chromatography (onsilica, ethyl acetate/hexane) provided the ester as a foam (910 mg,88%).

Part F: A solution of the ester of part E (910 mg, 1.64 mmol) in 4M HCl(5 mL) and methanol (12 drops) was stirred for 30 minutes. The solutionwas concentrated in vacuo. Reverse phase chromatography (on silica,acetonitrile/H₂O) provided the title compound as a white solid (260 mg,33%). MS(CI) MH⁺ calculated for C₂₄H₂₆N₂O₆S: 471, found 471.

EXAMPLE 11 (S)-1,1-Dimethylethyl[1-](hydroxyamino)-carbonyl-2,2-dimethyl-3-[(4-phenoxyphenyl)-sulfonyl]propyl]carbamate

Part A: To a solution of 4-(phenoxy)benzenethiol (9.8 g, 48.5 mmol) inDMF was added K₂CO₃ (6.7 g, 48.5 mmol) followed by R-pantolactone (6.3g, 48.4 mmol). The solution was heated to one hundred degrees Celsiusfor 3 hours followed by concentration in vacuo. The residue waspartitioned between ethyl acetate and 1N HCl . The organic layer wasdried over MgSO₄ and concentrated in vacuo. To a solution of the crudesulfide in methanol (200 mL) and H₂O (50 mL) was added Oxone® (90 g, 145mmol) and the solution was stirred for 18 hours. The mixture wasfiltered and the filtrate was concentrated and partitioned between ethylacetate and H₂O. The organic layer was concentrated and dried overMgSO₄. After concentration in vacuo the residue was dissolved inmethanol and treated with thionyl chloride (3.54 mL, 48.5 mmol). Thesolution was heated to reflux for 1 hour. Concentration in vacuoprovided the methyl ester sulfone as a white solid (8.45 g, 54%).

Part B: To a solution of the methyl ester sulfone of part A (4.0 g,10.57 mmol) in dichloromethane (50 mL) was added pyridine (1.1 mL, 13.33mmol) and the solution was cooled to minus seventy-five degrees Celsius.To this solution was added triflic anhydride (2.0 mL, 11.63 mmol)dropwise. The solution was stirred at ambient temperature for 2 hours.The solution was concentrated in vacuo and the residue was partitionedbetween ethyl acetate and H₂O. The organic layer was washed withsaturated NaHCO₃ and saturated NaCl and dried over Na₂SO₄. Concentrationin vacuo provided the triflate as a colored oil (5.4 g, quantitativeyield).

Part C: To a solution of the triflate of part B (5.4 g, 10.58 mmol) intoluene (100 mL) was added n-butyl ammonium azide (3.3 g, 11.64 mmol)and the solution was stirred at ambient temperature for 20 hours. Thesolution was concentrated in vacuo and the residue was partitionedbetween ethyl acetate and H₂O . The organic layer was washed withsaturated NaHCO₃, 5% citric acid and saturated NaCl and dried overNa₂SO₄. Concentration in vacuo provided the azide as an orange oil (7.4g).

Part D: To a solution of the azide of part C (4.3 g, 10.58 mmol) andp-toluenesulfonic acid monohydrate (2.0 g, 10.58 mmol) in methanol (80mL) was added 4% Pd/C and the solution was stirred for 1 hour under H₂at 50 psi. The solution continued to stir for 18 hours. The mixture wasfiltered through Celite and the filtrate was concentrated in vacuo toprovide the crude amine p-toluenesulfonic acid salt as a colored oil(9.3 g).

Part E: To a solution of the crude amine salt of part D (5.8 g, 10.55mmol) in THF (100 mL) was added di-t-butyl dicarbonate (2.5 g, 11.61mmol) and triethylamine (3.2 mL, 23.21 mmol). The solution was stirredat ambient temperature for 18 hours. The solution was concentrated invacuo and the residue was partitioned between ethyl acetate and H₂O. Theorganic layer was washed with 5% KHSO₄ and saturated NaCl and dried overMgSO₄. Chromatography (on silica, ethyl acetate/hexane) provide theprotected amine as a white foam (4.0 g, 87%).

Part F: To a solution of the protected amine of part E (1.0 g, 2.09mmol) in THF (10 mL) was added LiOH (400 mg, 8.38 mmol) in H₂O (10 mL)and the solution was stirred at ambient temperature for 6 hours. Thesolution was concentrated in vacuo and the residue was partitionedbetween ethyl acetate and 5% KHSO₄. The organic layer was washed withsaturated and dried over Na₂SO₄. Concentration in vacuo provided theacid as a white foam (1.0 g, quantitative yield).

Part G: To a solution of the acid of part F (1.0 g, 2.16 mmol) in DMF(10 mL) was added N-hydroxybenzotriazole (450 mg, 3.24 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (500 mg,2.59 mmol) and 50 aqueous hydroxylamine (2.5 mL) and was stirred atambient temperature for 1 hour. The solution was concentrated in vacuoand the residue partitioned between ethyl acetate and saturated NaHCO₃.The organic layer was washed with saturated NaCl and dried over Na₂SO₄.Reverse phase chromatography (on silica, acetonitrile/H₂O) provided thetitle compound as a white foam (700 mg, 70%). HPLC purity: 95%. MS(CI)MH⁺ calculated for C₂₃H₃₀N₂O₇S: 479, found 479.

EXAMPLE 12(S)-2-Amino-N-hydroxy-3,3-dimethyl-4-[(4-phenoxyphenyl)sulfonyl]butanamideMonohydrochloride

Part A: A solution of the hydroxamate of Example 11, part G (700 mg,1.46 mmol) in 4M HCl (10 mL) was stirred at ambient temperature for 1hour. The solution was concentrated in vacuo and tritration with ethylether provided the title compound as a white foam (600 mg, quantitativeyield). HPLC purity: 93%. MS(CI) MH⁺ calculated for C₁₈H₂₂N₂O₅S: 379,found 379.

EXAMPLE 13(S)-N-[1-[(Hydroxyamino)-carbonyl]-2,2-dimethyl-3-[(4-phenoxyphenyl)sulfonyl]-propyl]-4-morpholineacetamide

Part A: A solution of the methyl ester of Example 11, part E (1.84 g,3.85 mmol) in 4M HCl (20 mL) was stirred at ambient temperature for 1.5hour. The solution was concentrated in vacuo to provide the aminehydrochloride salt as a white foam (1.7 g, quantitative yield).

Part B: To a solution of the amine hydrochloride salt of part A (1.74 g,4.20 mmol) and diisopropylethylamine (1.7 mL, 9.46 mmol) indichloromethane (30 mL) cooled to zero degrees Celsius was addedchloroacetic anhydride (800 mg, 4.62 mmol) in dichloromethane (10 mL)and the solution was stirred at ambient temperature for 18 hours. Thesolution was concentrated in vacuo and the residue was partitionedbetween ethyl acetate and saturated NaHCO₃. The organic layer was washedwith 5% citric acid, H2O, and saturated NaCl and dried over Na₂SO₄.Chromatography (on silica, ethyl acetate/hexane) provided the chlorocompound as an off-white foam (1.5 g, 79%).

Part C: To a solution of the chloro compound of part B (1.5 g, 3.30mmol) in THF (10 mL) and H₂O (5 mL) was added morpholine (1.7 mL, 19.83mmol) and the solution was stirred at ambient temperature for 18 hours.The solution was concentrated in vacuo and the residue was partitionedbetween ethyl acetate and saturated NaHCO₃. The organic layer was washedwith saturated NaCl and dried over Na₂SO₄. Concentration in vacuoprovided the morpholine compound as a white foam (1.6 g, 94%).

Part D: To a solution of the morpholine compound of part C (1.6 g, 3.17mmol) in THF (10 mL) was added LiOH (530 mg, 12.68 mmol) in H₂O (10 mL)and the solution was stirred at ambient temperature for 2 hours. Thesolution was concentrated in vacuo. The residue was acidified to pH=6with dry ice and 5% KHSO₄ and extracted with ethyl acetate. The organiclayer was washed with saturated NaCl and dried over Na₂SO₄.Concentration in vacuo provided the acid as a white solid (1.4 g, 88%).

Part E: To a solution of the acid of part D (700 mg, 1.43 mmol) in DMF(10 mL) was added N-hydroxybenzotriazole (300 mg, 2.14 mmol),4-methylmorpholine (0.5 mL, 4.28 mmol), O-tetrahydropyranylhydroxylamine (500 mg, 4.42 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (400 mg,2.14 mmol) and the solution was stirred for 6 hours at ambienttemperature. The solution was concentrated in vacuo and the residue waspartitioned between ethyl acetate and H₂O and the organic layer waswashed with saturated NaCl and dried over Na₂SO₄. Chromatography (onsilica, ethyl acetate/hexane/methanol) provided the ester as a whitefoam (600 mg, 75%).

Part F: To a solution of the ester of part E (600 mg, 1.02 mmol) in1,4-dioxane (2 mL) was added 4M HCl in dioxane (5 mL) and the solutionwas stirred for 30 minutes. The solution was concentrated in vacuo.Reverse phase chromatography (on silica, acetonitrile/H₂O) provided thetitle compound as an off-white solid (400 mg, 72%). HPLC purity: 100%.MS(CI) MH⁺ calculated for C₂₄H₃₁N₃O₇S: 506, found 506. HRMS calculatedfor C₂₄H₃₁N₃O₇S: 506.1961, found 506.1955.

EXAMPLE 13a (S)-N-[1-[(Hydroxyamino)carbonyl]-2,2-dimethyl-3-[(4-phenoxyphenyl)sulfonyl]-propyl]-4-morpholineacetamideMonohydrochloride

To a solution of the hydroxamate of Example 13, part F (360 mg, 0.72mmol) in acetonitrile (10 mL) was added concentrated HCl (0.15 mL) andthe solution was stirred for 10 minutes. Concentration in vacuc followedby tritration with ether provided the hydrochloride salt a pink solid(260 mg, 67%). HPLC purity: 99.6%.

EXAMPLE 14(S)-N-[1-[(Hydroxyamino)carbonyl]-2,2-dimethyl-3-[4-phenoxy)sulfonyl]propyl]-1-pyrrolidineAcetamide Monohydrochloride

Part A: To a solution of the chloro compound of Example 13, part B (870mg, 1.9 mmol) in THF (10 mL) and H₂O (0.5 mL) was added pyrrolidine(0.95 mL, 11.4 mmol) and the solution was stirred for 2 hours. Thesolution was concentrated in vacuo and the residue was dissolved intoethyl acetate. Concentration in vacuo provided the pyrrolidine compoundas a white foam (930 mg, 93%)

Part B: To a solution of the pyrrolidine compound of part A (930 mg, 1.9mmol) in THF (10 mL) was added potassium trimethylsilanolate (300 mg,2.3 mmol) and the solution was stirred at ambient temperature for 18hours. The solution was concentrated in vacuo to provide the potassiumsalt of the acid as a white foam (1.03 g, quantitative yield).

Part C: To a solution of the acid salt of part B (1.02 g, 2.0 mmol) indichloromethane (10 mL) cooled to zero degrees Celsius was added4-methylmorpholine (0.61 mL, 6.0 mmol), O-tetrahydropyranylhydroxylamine (240 mg, 2.04 mmol) and PyBroP® (1.03 g, 2.2 mmol) and thesolution was stirred at ambient temperature for 18 hours. The solutionwas concentrated in vacuo. Chromatography (on silica, ethyl acetate/THF)followed by tritration with ethyl ether provided the ester as a whitefoam (250 mg, 22%).

Part D: A solution of the ester of part C (250 mg, 0.44 mmol) in 4M HClin dioxane (1 mL) and methanol (0.5 mL) was stirred for 30 minutes. Thesolution was concentrated in vacuo to provide the title compound as awhite solid (250 mg, quantitative yield). [Data to follow on 2/26]

EXAMPLE 15 N-Hydroxy-a-[2-[(4-phenoxyphenyl)sulfonyl]-ethyl]-1-piperidineacetamide Monohydrochloride

Part A: A solution of α-bromo-γ-lactone (10.13 g, 61.4 mmol) in pyridine(15.2 mL, 153 mmol) was stirred at ambient temperature for 2 days. Tothis solution was added dichloromethane (50 mL) followed by NaOH (2.46g, 61.4 mmol) in H₂O (20 mL). The solution was extracted withdichloromethane and washed with saturated NaCl and dried over MgSO₄.Vacuum distillation provided the pyridyl lactone as a yellow oil (7.093g, 68%).

Part B: To a slurry of NaH (60% suspension in mineral oil) in DMF (44mL) cooled to 0° C. was added 4-(phenoxy)benzenethiol (5.87 g, 29.0mmol). After 15 minutes the pyridyl lactone of part A (3.78 g, 22.3mmol) was added and the solution was heated to eighty-seven degreesCelsius for 16 hours. The solution was concentrated in vacuo and theresidue was partitioned between 2N HCl and ethyl ether and the aqueouswas extracted with ethyl ether. The aqueous layer was concentrated invacuo and the resulting oil crystallized upon standing to provide thesulfide hydrochloride salt as a white solid (4.07 g, 45%).

Part C: To a solution of the sulfide of part B (1.206 g, 2.96 mmol) inDMF (10 mL) was added 4-methylmorpholine (1.30 mL, 11.8 g),N-hydroxybenzotriazole (480 mg, 3.55 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (737 mg,3.84 mmol) and O-tetrahydropyranyl hydroxylamine (485 g, 4.14 mmol) andthe solution stirred for 18 hours at ambient temperature. The solutionwas concentrated in vacuo and the residue was partitioned betweendichloromethane and H₂O. The organic layer was washed with H₂O andsaturated NaCl and dried over Na₂SO₄. Chromatography (on silica,methanol(NH₃)/dichloromethane) provided the ester as a colorless oil(1.08 g, 77%). MS(CI) MH⁺ calculated for C₂₆H₃₄N₂O₄S: 471, found 471.Analytical calculation for C₂₆H₃₄N₂O₄S: C, 66.35; H, 7.28; N, 5.95; S,6.81. Found: C, 65.97; H, 7.51; N, 5.98; S, 6.91.

Part D: To a solution of the ester of part C (234 mg, 0.50 mmol) indichloromethane (3 mL) was added p-toluenesulfonic acid (95 mg, 0.50mmol) followed by 3-chloroperbenzoic acid (57-86%, 257 mg, 1.50 mmol)and the solution stirred for 1.5 hours at ambient temperature. Thesolution was diluted with dichloromethane and washed with 10% Na₂CO₃,saturated NaHCO₃, H₂O and saturated NaCl and dried over Na₂SO₄.Chromatography (on silica, methanol(NH₃)/dichloromethane) provided thesulfone as a colorless oil (101 mg, 40%). MS(CI) MH⁺ calculated forC₂₆H₃₄N₂O₆S: 503, found 503.

Part E: To a solution of the sulfone of part D (100 mg, 0.20 mmol) inmethanol (2 mL) was added acetyl chloride (0.038 mL, 0.60 mmol) and thesolution was stirred for 17 hours at ambient temperature. The solutionwas concentrated and the residue was diluted in ethyl acetate. Theresulting precipitate was washed with ethyl acetate to provide the titlecompound as a white solid (62 mg, 69%). MS(CI) MH⁺ calculated forC₂₁H₂₆N₂O₅S: 419, found 419. Analytical calculation for C₂₁H₂₆N₂O₅S·HCl:C, 55.44; H, 5.98; N. 6.16; Cl, 7.79. Found: C, 55.60; H, 6.24; N, 6.03;Cl, 7.65.

EXAMPLE 16 1,1-Dimethylethyl Ester4-[(Hydroxyamino)-carbonyl]-4-[2-[(4-phenoxyphenyl)sulfonyl]-ethyl]-1-piperidinecarboxylicAcid

Part A: To a solution of ethyl isonipecotate (15.7 g, 0.1 mol) intetrahydrofuran (100 mL) was added a solution of di-tert-butyldicarbonate (21.8 g, 0.1 mol) in THF (5 mL) dropwise over 20 minutes.The solution stirred overnight at ambient temperature and concentratedin vacuo to yield a light oil. The oil was filtered through silica gel(7:3 ethyl acetate/hexane) and concentrated in vacuo to give theBOC-piperidine compound (26.2 g, quantitative yield) as a clear,colorless oil.

Part B: To a solution of the BOC-piperidine of part A (5.14 g, 20.0mmol) in THF (60 mL) cooled to −50° C. was added lithium diusopropylamide (1.8 M in THF, 11.1 mL, 20.0 mmol). The solution stirred for 1hour followed by the addition of 1-bromo-2-chloroethane (1.66 mL, 20.0mmol). After stirring at −40° C. for 15 minutes, the solution returnedto ambient temperature for 4 hours. The reaction was quenched with H₂Oand extracted with ethyl acetate and the organic layer was washed withH₂O and satd. NaCl, and dried over MgSO₄. Concentration in vacuoprovided the chlorinated compound as a yellow oil (5.98 g, 93%).

Part C: To a cooled (0° C.) suspension of sodium hydride (120 mg as a60% dispersion in mineral oil, 3.0 mmol) in DMF (4 mL) was added4-(phenoxy)benzenethiol (607 mg, 3.0 mmol) in DMF (2 mL) and thesolution stirred for 15 minutes. To this solution was added thechlorinated compound of part A (960 mg, 3.0 mmol) in DMF (5 mL) and thesolution stirred at ambient temperature for 4 hours. The solution waspartitioned between ethyl acetate and H₂O and the organic was washedwith 15% KHSO₄ and satd. NaCl and dried over MgSO₄. Chromatography (1:9ethyl acetate/hexane) provided the sulfide as an oil (1.26 g, 87%).

Part D: To a solution of the sulfide of Part C (1.25 g, 2.6 mmol) indichloromethane (20 mL) cooled to 0° C., was added 3-chloroperbenzoicacid (80%, 1.11 g, 5.1 mmol). The solution stirred at ambienttemperature for 2.5 hours. Additional dichloromethane was added and theorganic layer was washed with H₂O, satd. NaHCO₃, and satd. NaCl anddried over MgSO₄. Chromatography (20 ethyl acetate/80 hexane) providedthe sulfone as a solid (740 mg, 56%). MS(CI) MH⁺ calcd. for C₂₇H₃₅NO₇S:518, found 518. HRMS calcd. for C₂₇H₃₅NO₇S: 518.2212, found 518.2222.

Part E: To a solution of the sulfone of Part D (708 mg, 1.37 mmol) inTHF (5 mL) and ethanol (5 mL) was added sodium hydroxide (547 mg, 13.7mmol) in H₂O (7 mL). The solution was heated to 65° C. for 18 hours. Thesolution was concentrated in vacuo and the residue was suspended in H₂Oand acidified with 2N HCl. The solution was extracted with ethyl acetateand the organic layer was washed with sat. NaCl and dried over MgSO₄.Concentration in vacuo provided the acid as a light yellow foam (500 mg,75%). MS(CI) MH⁺ calcd. for C₂₅H₃₁NO₇S: , found. HRMS calcd. forC₂₅H₃₁NO₇S: , found. Anal. calcd. for C₂₅H_(b31)NO₇S 0.3H₂O: C, 60.66;H, 6.43; N, 2.83; S, 6.48. Found: C, 60.20; H, 6.59; N, 2.63; S, 5.85.

Part F: To a solution of the acid of part E (475 mg, 0.97 mmol) in DMF(10 mL) was added N-hydroxybenzotriazole·H₂O (157 mg, 1.16 mmol)followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride(260 mg, 1.36 mmol). After 5 minutes of stirring at ambienttemperature 4-methylmorpholine (0.32 mL, 2.91 mmol) was added followedby 50% aqueous NH₂OH (0.192 mL, 2.91 mmol). The solution stirred for 7hours. Additional N-hydroxybenzotriazole·H₂O (157 mg),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (260 mg),4-methylmorpholine (0.32 mL) and 50% aqueous NH₂OH were added and thesolution stirred for 48 hours. The solution was diluted with H₂O,extracted with ethyl acetate and washed with satd. NaCl and dried overMgSO₄. Reverse phase HPLC (acetonitrile/H₂O) provided the title compoundas a white solid (228 mg, 47%). HPLC purity: >99%. MS(CI) MH⁺ calcd. forC₂₅H₃₂N₂O₇S: 505, found 505. Anal. calcd. for C₂₅H₃₂N₂O₇S·0.25H₂O: C,58.98; H, 6.43; N, 5.50. Found: C, 58.87; H, 6.40; N, 5.38.

EXAMPLE 17 N-Hydroxy-4-[2-[(4-phenoxyphenyl)sulfonyl]-ethyl]-4-piperidine carboxamide, Monohydrochloride

Part A; To a solution of ethyl isonipecotate (15.7 g, 0.1 mol) intetrahydrofuran (100 mL) was added a solution of di-tert-butyldicarbonate (21.8 g, 0.1 mol) in THF (5 mL) dropwise over 20 minutes.The solution stirred overnight at ambient temperature and concentratedin vacuo to yield a light oil. The oil was filtered through silica gel(7:3 ethyl acetate/hexane) and concentrated in vacuo to give theBOC-piperidine compound (26.2 g, quantitative yield) as a clear,colorless oil.

Part B: To a solution of the BOC-piperidine of part A (5.14 g, 20.0mmol) in THF (60 mL) cooled to −50° C. was added lithium diisopropylamide (1.8 M in THF, 11.1 mL, 20.0 mmol). The solution stirred for 1hour followed by the addition of 1-bromo-2-chloroethane (1.66 mL, 20.0mmol). After stirring at −40° C. for 15 minutes, the solution returnedto ambient temperature for 4 hours. The reaction was quenched with H₂Oand extracted with ethyl acetate and the organic layer was washed withH₂O and satd. NaCl, and dried over MgSO₄. Concentration in vacuoprovided the chlorinated compound as a yellow oil (5.98 g, 93%).

Part C: To a cooled (0° C.) suspension of sodium hydride (120 mg as a60% dispersion in mineral oil, 3.0 mmol) in DMF (4 mL) was added4-(phenoxy)benzene (607 mg, 3.0 mmol) in DMF (2 mL) and the solutionstirred for 15 minutes. To this solution was added the chlorinatedcompound of part A (960 mg, 3.0 mmol) in DMF (5 mL) and the solutionstirred at ambient temperature for 4 hours. The solution was partitionedbetween ethyl acetate and H₂O and the organic was washed with 15% KHSO₄and satd. NaCl and dried over MgSO₄. Chromatography (1:9 ethylacetate/hexane) provided the sulfide as an oil (1.26 g, 87%).

Part D: To a solution of the sulfide of Part C (1.25 g, 2.6 mmol) indichloromethane (20 mL) cooled to 0° C., was added 3-chloroperbenzoicacid (80%, 1.11 g, 5.1 mmol). The solution stirred at ambienttemperature for 2.5 hours. Additional dichloromethane was added and theorganic layer was washed with H₂O, satd. NaHCO₃, and satd. NaCl anddried over MgSO₄. Chromatography (20 ethyl acetate/80 hexane) providedthe sulfone as a solid (740 mg, 56%). HRMS calcd. for C₂₇H₃₅NO₇S:518.2212, found 518.2222.

Part E: To a solution of the sulfone of Part D (708 mg, 1.37 mmol) inTHF (5 mL) and ethanol (5 mL) was added sodium hydroxide (547 mg, 13.7mmol) in H₂O (7 mL). The solution was heated to 65° C. for 18 hours. Thesolution was concentrated in vacuo and the residue was suspended in H₂Oand acidified with 2N HCl. The solution was extracted with ethyl acetateand the organic layer was washed with satd. NaCl and dried over MgSO₄.Concentration in vacuo provided the acid as a light yellow foam (500 mg,75%). Anal. calcd. for C₂₅H₃₁NO₇S·0.3H₂O: C, 60.64; H, 6.43; N, 2.83; S,6.48. Found: C, 60.20; H, 6.59; N, 2.63; S, 5.85.

Part F: To a solution of the acid of part E (475 mg, 0.97 mmol) in DMF(10 mL) was added N-hydroxybenzotriazole·H₂O (157 mg, 1.16 mmol)followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(260 mg, 1.36 mmol). After 5 minutes of stirring at ambient temperature4-methylmorpholine (0.32 mL, 2.91 mmol) was added followed by 50%aqueous NH₂OH (0.192 mL, 2.91 mmol). The solution stirred for 7 hours.Additional N-hydroxybenzotriazole·H₂O (157mg),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (260mg), 4-methylmorpholine (0.32 mL) and 50% aqueous NH₂OH were added andthe solution stirred for 48 hours. The solution was diluted with H₂O,extracted with ethyl acetate and washed with satd. NaCl and dried overMgSO₄. Reverse phase HPLC (acetonitrile/H₂O) provided the hydroxamate asa white solid (228 mg, 47%). Anal. calcd. for C₂₅H₃₂N₂O₇S·0.25H₂O: C,58.98; H, 6.43; N, 5.50. Found: C, 58.87; H, 6.40; N, 5.38.

Part G: To a cooled (0° C.) solution of the BOC-hydroxamate of Part F(205 mg, 0.41 mmol) was bubbled HCl gas for 5 minutes followed bystanding for 1 hour. Concentration followed by trituration with ethylether provided the title compound as a white solid (183 mg, quantitativeyield). MS (CI) MH⁺ calcd. for C₂₀H₂₄N₂O₅S: 405, found 405. HRMS calcd.for C₂₀H₂₄N₂O₅S: 405.1484, found 405.1484. Anal. calcd. for C₂₀H₂₄N₂O₅SHCl H₂O: C, 52.34; H, 5.97; N, 6.10; Cl, 7.72. Found: C, 52.07; H, 5.97;N, 5.85; Cl, 8.04.

EXAMPLE 18 In Vitro Metalloprotease Inhibition

Several of the compounds prepared in the manner described in Examples 1to 17 were assayed for activity by an in vitro assay. Following theprocedures of Knight et al., FEBS Lett. 296(3):263 (1992). Briefly,4-aminophenylmercuric acetate (APMA) or trypsin activated MMPs wereincubated with various concentrations of the inhibitor compound at roomtemperature for 5 minutes.

More specifically, recombinant human MMP-13 and MMP-1 enzymes wereprepared in laboratories of the assignee. MMP-13 was expressed inbaculovirus as a proenzyme, and purified first over a heparin agarosecolumn and then over a chelating zinc chloride column. The proenzyme wasactivated by APMA for use in the assay. MMP-1 expressed in transfectedHT-1080 cells was provided by Dr. Howard Welgus of WashingtonUniversity, St. Louis, Mo. The enzyme was also activated using APMA andwas then purified over a hydroxamic acid column.

The enzyme substrate is a methoxycoumarin-containing polypeptide havingthe following sequence:

MCA-ProLeuGlyLeuDpaAlaArgNH², wherein MCA is methoxycoumarin and Dpa is3-(2,4-dinitrophenyl)-L-2,3-diaminopropionyl alanine. This substrate iscommercially available from Baychem as product M-1895.

The buffer used for assays contained 100 mM Tris-HCl, 100 mM NaCl, 10 mMCaCl₂ and 0.05 percent polyethyleneglycol (23) lauryl ether at a pHvalue of 7.5. Assays were carried out at room temperature, and dimethylsulfoxide (DMSO) at a final concentration of 1 percent was used todissolve inhibitor compound.

The assayed inhibitor compound in DMSO/buffer solution was compared toan equal amount of DMSO/buffer with no inhibitor as control usingMicrofluor™ White Plates (Dynatech). The inhibitor or control solutionwas maintained in the plate for 10 minutes and the substrate was addedto provide a final concentration of 4 μM.

In the absence of inhibitor activity, a fluorogenic peptide was cleavedat the gly-leu peptide bond, separating the highly fluorogenic peptidefrom a 2,4-dinitrophenyl quencher, resulting in an increase offluorescence intensity (excitation at 328 nm/emission at 415 nm).Inhibition was measured as a reduction in fluorescent intensity as afunction of inhibitor concentration, using a Perkin Elmer L550 platereader. The IC₅₀ values were calculated from those values. The resultsare set forth in the Inhibition Table below, reported in terms of IC₅₀to three significant figures.

TABLE 37 Inhibition Table (IC₅₀ values in nM) Example MMP-13 MMP-1 MMP-21 1.9 6300 0.3 2 8.8 >10,000 2.0 3 2600 >10,000 1000 4 54.4 >10,000 15.85 1.8 >10,000 3.2 6 2000 7 400 >10,000 120  8a 5.0 >10,000 2.2  9a 3.07000 1.3 10 2.4 10,000 1.5 11 <0.1 50 <0.1 12 1.6 3300 0.3 13 1.4 7700.3 13a 1.8 1800 0.6 14 2.4 >10,000 1.8 15 13.9 >10,000 7.7 16400 >10,000 169 17 169 >10,000 70

EXAMPLE 19 In Vivo Angiogenesis Assay

The study of angiogenesis depends on a reliable and reproducible modelfor the stimulation and inhibition of a neovascular response. Thecorneal micpocket assay provides such a model of angiogenesis in thecornea of a mouse. See, A Model of Angiogenesis in the Mouse Cornea;Kenyon,BM, et al., Investigative Ophthalmology & Visual Science, July1996, Vol. 37, No. 8.

In this assay, uniformly sized Hydron™ pellets containing bFGF andsucralfate are prepared and surgically implanted into the stroma mousecornea adjacent to the temporal limbus. The pellets are formed by makinga suspension of 20 μL sterile saline containing 10 μg recombinant bFGF,10 mg of sucralfate and 10 μL of 12 percent Hydron™ in ethanol. Theslurry is then deposited on a 10×10 mm piece of sterile nylon mesh.After drying, the nylon fibers of the mesh are separated to release thepellets.

The corneal pocket is made by anesthetizing a 7 week old C57Bl/6 femalemouse, then proptosing the eye with a jeweler's forceps. Using adissecting microscope, a central, intrastromal linear keratotomy ofapproximately 0.6 mm in length is performed with a #15 surgical blade,parallel to the insertion of the lateral rectus muscle. Using a modifiedcataract knife, a lamellar micropocket is dissected toward the temporallimbus. The pocket is extended to within 1.0 mm of the temporal limbus.A single pellet is placed on the corneal surface at the base of thepocket with a jeweler's forceps. The pellet is then advanced to thetemporal end of the pocket. Antibiotic ointment is then applied to theeye.

Mice are dosed on a daily basis for the duration of the assay. Dosing ofthe animals is based on bioavailability and overall potency of thecompound. an exemplary dose is 50 mg/kg bid, po. Neovascularization ofthe corneal stroma begins at about day three and is permitted tocontinue under the influence of the assayed compound until day five. Atday five, the degree of angiogenic inhibition is scored by viewing theneovascular progression with a slit lamp microscope.

The mice are anesthetized and the studied eye is once again proptosed.The maximum vessel length of neovascularization, extending from thelimbal vascular plexus toward the pellet is measured. In addition, thecontiguous circumferential zone of neovascularization is measured asclock hours, where 30 degrees of arc equals one clock hour. The area ofangiogenesis is calculated as follows.${area} = \frac{\left( {0.4 \times {clock}\quad {hours} \times 3.14 \times {vessel}\quad {length}\quad \left( {{in}\quad {mm}} \right)} \right)}{2}$

The studied mice are thereafter compared to control mice and thedifference in the area of neovascularization is recorded. A contemplatedcompound typically exhibits about 25 to about 75 percent inhibition,whereas the vehicle control exhibits zero percent inhibition.

From the foregoing, it will be observed that numerous modifications andvariations can be effectuated without departing from the true spirit andscope of the novel concepts of the present invention. It is to beunderstood that no limitation with respect to the specific examplepresented is intended or should be inferred. The disclosure is intendedto cover by the appended claims all such modifications as fall withinthe scope of the claims.

What is claimed is:
 1. A compound or a salt thereof, wherein: thecompound corresponds in structure to Formula I:

R¹ is a substituted 5- or 6-membered cyclohydrocarbyl, heterocyclo,aryl, or heteroaryl; the number of non-hydrogen atoms in the longestlinear chain of atoms in R¹ is greater than 6 and less than about 20atoms; R¹ defines a three-dimensional volume, when rotated about an axisdrawn through the SO₂-bonded 1-position and the 4-position of a6-membered ring or drawn through the SO₂-bonded 1-position and thecenter of the 3,4-bond of a 5-membered ring, whose widest dimension in adirection transverse to the axis of rotation is about that of onefuranyl ring to about that of two phenyl rings; as to R² and R³: R¹ andR³ are independently selected from the group consisting of hydrido,C₁-C₄ hydrocarbyl, heteroaryl-C₁-C₄ hydrocarbyl, aryl-C₁-C₄ hydrocarbyl,hydroxy-C₁-C₄ hydrocarbyl, C₁-C₄ hydrocarbyloxy-C₁-C₄ hydrocarbyl,aryloxy-C₁-C₄ hydrocarbyl, amino-C₁-C₄ hydrocarbyl, C₁-C₄hydrocarbylthio-C₁-C₄ hydrocarbyl, C₁-C₄ hydrocarbylsulfonyl-C₁-C₄hydrocarbyl, aminosulfonylamino-C₁-C₄ hydrocarbyl,aminocarbonylamino-C₁-C₄ hydrocarbyl, C₁-C₄hydrocarbylcarbonylamino-C₁-C₄ hydrocarbyl, aryl-C₁-C₄ hydrocarbyl,heteroaryl-C₁-C₄ hydrocarbyl, and benzyloxy-C₁-C₄ hydrocarbyl, exceptthat only one of R² and R³ may be other than hydrido or C₁-C₄hydrocarbyl, or R² and R³, together with the depicted carbon atom towhich they are bonded, form a heterocyclic ring, wherein each heteroatomin the heterocyclic ring is: independently selected from the groupconsisting of oxygen, sulfur, and nitrogen, when sulfur, optionallysubstituted with one or two oxygens, and when nitrogen, optionallysubstituted with a substituent, R⁵, that is selected from the groupconsisting of hydrido, C₁-C₄ hydrocarbyl, C₃-C₆ cyclohydrocarbyl, C₁-C₄hydrocarbylcarbonyl, and C₁-C₄ hydrocarbyl sulfonyl; as to R⁶ and R⁷: R⁶and R⁷ are independently selected from the group consisting of hydrido,C₁-C₄ hydrocarbyl, heteroaryl-C₁-C₄ hydrocarbyl, aryl-C₁-C₄ hydrocarbyl,hydroxy-C₁-C₄ hydrocarbyl, C₁-C₄ hydrocarbyloxy-C₁-C₄ hydrocarbyl,aryloxy-C₁-C₄ hydrocarbyl, amino-C₁-C₄ hydrocarbyl, C₁-C₄hydrocarbylthio-C₁-C₄ hydrocarbyl, C₁-C₄ hydrocarbylsulfonyl-C₁-C₄hydrocarbyl, aminosulfonylamino-C₁-C₄ hydrocarbyl,aminocarbonylamino-C₁-C₄ hydrocarbyl, C₁-C₄hydrocarbylcarbonylamino-C₁-C₄ hydrocarbyl, aryl-C₁-C₄ hydrocarbyl,heteroaryl-C₁-C₄ hydrocarbyl, and benzyloxy-C₁-C₄ hydrocarbyl, exceptthat only one of R⁶ and R⁷ may be other than hydrido or C₁-C₄hydrocarbyl, or R⁶ and R⁷, together with the depicted carbon atom towhich they are bonded, form a heterocyclic ring, wherein each heteroatomin the heterocyclic ring is: independently selected from the groupconsisting of oxygen, sulfur, and nitrogen, when sulfur, optionallysubstituted with one or two oxygens, and when nitrogen, optionallysubstituted with a substituent, R⁵, that is selected from the groupconsisting of hydrido, C₁-C₄ hydrocarbyl, C₃-C₆ cyclohydrocarbyl, C₁-C₄hydrocarbylcarbonyl, and C₁-C₄ hydrocarbylsulfonyl; and only one of R²,R³, R⁶, and R⁷ may be other than hydrido, C₁-C₄ hydrocarbyl, or a partof a heterocyclic ring structure.
 2. The compound or salt according toclaim 1, wherein: said 5- or 6-membered cyclohydrocarbyl, heterocyclo,aryl, or heteroaryl of R¹ is substituted with a substituent, R⁴; and thenumber of non-hydrogen atoms in the longest linear chain of atoms in R⁴is from 3 to about 14 atoms.
 3. The compound or salt according to claim2, wherein R⁴ is selected from the group consisting of phenyl, phenoxy,thiophenoxy, anilino, phenylazo, phenylureido, benzamido, nicotinamido,isonicotinamido, picolinamido, heterocyclo, heterocyclohydrocarbyl,arylheterocyclohydrocarbyl, arylhydrocarbyl, heteroarylhydrocarbyl,heteroarylheterocyclohydrocarbyl, arylhydrocarbyloxyhydrocarbyl,aryloxyhydrocarbyl, hydrocarboylhydrocarbyl,arylhydrocarboylhydrocarbyl, arylcarbonylhydrocarbyl, arylazoaryl,arylhydrazinoaryl, hydrocarbylthiohydrocarbyl, hydrocarbylthioaryl,arylthiohydrocarbyl, heteroarylthiohydrocarbyl,hydrocarbylthioarylhydrocarbyl, arylhydrocarbylthiohydrocarbyl,arylhydrocarbylthioaryl, arylhydrocarbylamino,heteroarylhydrocarbylamino, and heteroarylthio.
 4. The compound or saltaccording to claim 2, wherein R⁴ is selected from the group consistingof phenyl, phenoxy, thiophenoxy, anilino, phenylazo, phenylureido,benzamido, nicotinamido, isonicotinamido, picolinamido, heterocyclo,heterocyclohydrocarbyl, arylheterocyclohydrocarbyl, arylhydrocarbyl,heteroarylhydrocarbyl, heteroarylheterocyclohydrocarbyl,arylhydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl,hydrocarboylhydrocarbyl, arylhydrocarboylhydrocarbyl,arylcarbonylhydrocarbyl, arylazoaryl, arylhydrazinoaryl,hydrocarbylthiohydrocarbyl, hydrocarbylthioaryl, arylthiohydrocarbyl,heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl,arylhydrocarbylthiohydrocarbyl, arylhydrocarbylthioaryl,arylhydrocarbylamino, heteroarylhydrocarbylamino, and heteroarylthio,wherein: any such substituent is itself substituted by one or moresubstituents independently selected from the group consisting ofhalogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano,perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy, mercapto,hydroxycarbonyl, aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl,heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl,hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy,hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino,cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino,heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio,heteroarylhydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio,arylhydrocarbylamino, heterocyclic, heteroaryl,hydroxycarbonylhydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbyloyl,arylcarbonyl, arylhydrocarbyloyl, hydrocarboyloxy, arylhydrocarboyloxy,hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio,hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl,hydroxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyl,hydrocarbylhydroxycarbonylhydrocarbylthio,hydrocarbyloxycarbonylhydrocarbyloxy,hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino,arylcarbonylamino, cyclohydrocarbylcarbonylamino,heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino,heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino,heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino,arylhydrocarbylsulfonylamino, heteroarylsulfonylamino,heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino,heterocyclohydrocarbylsulfonylamino, and aminohydrocarbyl, wherein: theaminohydrocarbyl nitrogen is substituted by one or two substituentsindependently selected from the group consisting of hydrocarbyl, aryl,arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl,hydrocarbyloxycarbonyl, and hydrocarboyl, or the aminohydrocarbylnitrogen is substituted with two substituents such that the twosubstituents, together with the aminohydrocarbyl nitrogen, form a 5- to8-membered heterocyclic or heteroaryl ring.
 5. A compound or a saltthereof, wherein: the compound corresponds in structure to Formula I:

R¹ is cyclohydrocarbyl, heterocyclo, aryl, or heteroaryl. wherein suchsubstituent: has 5 or 6 ring members, and is substituted at its own4-position when a 6-membered ring and at its own 3- or 4-position when a5-membered ring with a substituent, R⁴; R⁴ is selected from the groupconsisting of single-ringed cyclohydrocarbyl, single-ringed heterocyclo,single-ringed aryl, single-ringed heteroaryl, C₃-C₁₄ hydrocarbyl, C₂-C₁₄hydrocarbyloxy, phenoxy, thiophenoxy group, 4-thiopyridyl, phenylazo,phenylureido, nicotinamido, isonicotinamido, picolinamido, anilino, andbenzamido; as to R² and R³: R³ is selected from the group consisting ofhydrido and C₁-C₄ hydrocarbyl; and R² is selected from the groupconsisting of hydrido, C₁-C₄ hydrocarbyl, N-piperidinyl, N-piperazinyl,N-(C₁-C₄ hydrocarbyl)piperazinyl, N-pyrrolidinyl, N-morpholinyl, and—Y—Z, or R² and R³, together with the depicted carbon atom to which theyare bonded, form a 6-membered heterocyclic ring, wherein each heteroatomin the heterocyclic ring is: independently selected from the groupconsisting of oxygen, sulfur, and nitrogen, when sulfur, optionallysubstituted with one or two oxygens, and when nitrogen, optionallysubstituted with a substituent selected from the group consisting ofC₁-C₄ hydrocarbyl, C₃-C₆ cyclohydrocarbyl, C₁-C₄ hydrocarbylcarbonyl,and C₁-C₄ hydrocarbylsulfonyl; as to R⁶ and R⁷: R⁷ is independentlyselected from the group consisting of hydrido and C₁-C₄ hydrocarbyl; andR⁶ is selected from the group consisting of hydrido, C₁-C₄ hydrocarbyl,N-piperidinyl, N-piperazinyl, N-(C₁-C₄ hydrocarbyl)piperazinyl,N-pyrrolidinyl, N-morpholinyl, and —Y—Z, or R⁶ and R⁷, together with thedepicted carbon atom to which they are bonded, form a 6-memberedheterocyclic ring wherein each heteroatom in the heterocyclic ring is:independently selected from the group consisting of oxygen, sulfur, andnitrogen, when sulfur, optionally substituted with one or two oxygens,and when nitrogen, optionally substituted with a substituent selectedfrom the group consisting of C₁-C₄ hydrocarbyl, C₃-C₆ cyclohydrocarbyl,C₁-C₄ hydrocarbylcarbonyl, and C₁-C₄ hydrocarbylsulfonyl; each —Y isindependently selected from the group consisting of —O and —NR¹¹; eachR¹¹ is independently selected from the group consisting of hydrido andC₁-C₄ hydrocarbyl; each —Z is independently selected from the groupconsisting of hydrido, C₁-C₄ hydrocarbyl, benzoyl, (2-pyridinyl)methyl,(3-pyridinyl)methyl, (4-pyridinyl)methyl, 2-(morpholinyl)ethyl,2-(piperidinyl)ethyl, 2-(piperazinyl)ethyl,2-(N-methylpiperazinyl)ethyl, 2-(thiomorpholinyl)ethyl,2-(thiomorpholinyl sulfone)ethyl, 2-(succinimidyl)ethyl,2-(hydantoinyl), 2-(3-methylhydantoinyl)ethyl, 2-(N-C₁-C₄hydrocarbylamino)ethyl, 2-[N,N-di(C₁-C₄ hydrocarbyl)amino]ethyl, carboxyC₁-C₄ hydrocarbyl, piperidinyl, 2-pyridinyl, 3-pynidinyl, 4-pyndinyl,sulfonamido, C₁-C₄ hydrocarbylsulfonyl, C₁-C₄ hydrocarbylphosphonyl, and—C(O)—W; each —W is independently selected from the group consisting ofhydrido, C₁-C₄ hydrocarbyl, C₁-C₄ hydrocarbyloxy, and —CHR¹²NH₂; eachR¹² is independently selected from the group consisting of a side chainof a D amino acid, a side chain of an L amino acid, benzyloxy,benzylamino, and amino; and only one of R², R³, R⁶, and R⁷ may be otherthan hydrido, C₁-C₄ hydrocarbyl, or a part of a heterocyclic ringstructure.
 6. A compound or a salt thereof, wherein: the compoundcorresponds in structure to Formula I:

R¹ is phenyl substituted with R⁴ at the 4-position; and R⁴ is selectedfrom the group consisting of phenyl, phenoxy, thiophenoxy, phenylazo,benzamido, anilino, nicotinamido, isonicotinamido, picolinamido, andphenylureido, wherein any such substituent is optionally substituted: atthe meta- or para-position or both with a substituent that is selectedfrom the group consisting of halogen, C₁-C₉ hydrocarbyloxy, C₁-C₁₀hydrocarbyl, di-C₁-C₉ hydrocarbylamino, carboxyl C₁-C₈ hydrocarbyl,C₁-C₄ hydrocarbyloxy carbonyl C₁-C₄ hydrocarbyl, C₁-C₄hydrocarbyloxycarbonyl C₁-C₄ hydrocarbyl, and carboxamido C₁-C₈hydrocarbyl, or at the meta- and para-positions by two methyl groups orby a methylenedioxy group; as to R² and R³: R³ is selected from thegroup consisting of hydrido and C₁-C₄ hydrocarbyl; and R² is selectedfrom the group consisting of hydrido, C₁-C₄ hydrocarbyl, N-piperidinyl,N-piperazinyl, N-(C₁-C₄ hydrocarbyl)piperazinyl, N-pyrrolidinyl,N-morpholinyl, and —Y—Z, or R² and R³, together with the depicted carbonatom to which they are bonded, form a 6-membered heterocyclic ring,wherein each heteroatom in the heterocyclic ring is: independentlyselected from the group consisting of oxygen, sulfur, and nitrogen, whensulfur, optionally substituted with one or two oxygens, and whennitrogen, optionally substituted with a substituent selected from thegroup consisting of C₁-C₄ hydrocarbyl, C₃-C₆ cyclohydrocarbyl, C₁-C₄hydrocarbylcarbonyl, and C₁-C₄ hydrocarbylsulfonyl; as to R⁶ and R⁷: R⁷is independently selected from the group consisting of hydrido and C₁-C₄hydrocarbyl; and R⁶ is selected from the group consisting of hydrido,C₁-C₄ hydrocarbyl, N-piperidinyl, N-piperazinyl, N-(C₁-C₄hydrocarbyl)piperazinyl, N-pyrrolidinyl, N-morpholinyl, and —Y—Z, or R⁶and R⁷, together with the depicted carbon atom to which they are bonded,form a 6-membered heterocyclic ring wherein each heteroatom in theheterocyclic ring is: independently selected from the group consistingof oxygen, sulfur, and nitrogen, when sulfur, optionally substitutedwith one or two oxygens, and when nitrogen, optionally substituted witha substituent selected from the group consisting of C₁-C₄ hydrocarbyl,C₃-C₆ cyclohydrocarbyl, C₁-C₄ hydrocarbylcarbonyl, and C₁-C₄hydrocarbylsulfonyl; each —Y is independently selected from the groupconsisting of —O and —NR¹¹; each R¹¹ is independently selected from thegroup consisting of hydrido and C₁-C₄ hydrocarbyl; each —Z isindependently selected from the group consisting of hydrido, C₁-C₄hydrocarbyl, benzoyl, (2-pyridinyl)methyl, (3-pyridinyl)methyl,(4-pyridinyl)methyl, 2-(morpholinyl)ethyl, 2-(piperidinyl)ethyl,2-(piperazinyl)ethyl, 2-(N-methylpiperazinyl)ethyl,2-(thiomorpholinyl)ethyl, 2-(thiomorpholinyl sulfone)ethyl,2-(succinimidyl)ethyl, 2-(hydantoinyl), 2-(3-methylhydantoinyl)ethyl,2-(N-C₁-C₄ hydrocarbylamino)ethyl, 2-[N,N-di(C₁-C₄hydrocarbyl)amino]ethyl, carboxy C₁-C₄ hydrocarbyl, piperidinyl,2-pyridinyl, 3-pyridinyl, 4-pyridinyl, sulfonamido, C₁-C₄hydrocarbylsulfonyl, C₁-C₄ hydrocarbylphosphonyl, and —C(O)—W; each —Wis independently selected from the group consisting of hydrido, C₁-C₄hydrocarbyl, C₁-C₄ hydrocarbyloxy, and —CHR₁₂NH₂; each R¹² isindependently selected from the group consisting of a side chain of a Damino acid, a side chain of an L amino acid, benzyloxy, benzylamino, andamino; and only one of R², R³, R⁶, and R⁷ may be other than hydrido,C₁-C₄ hydrocarbyl, or a part of a heterocyclic ring structure.
 7. Thecompound or salt according to claim 5 wherein R⁶ and R⁷ are bothhydrido.
 8. The compound or salt according to claim 5 wherein R⁶ and R⁷are both methyl.
 9. The compound or salt according to claim 5, whereinthe number of non-hydrogen atoms in the longest linear chain of atoms inR¹ is greater than 8 and less than 18 atoms.
 10. A compound or a saltthereof, wherein: the compound corresponds in structure to Formula II:

PhR⁴ is phenyl substituted at its 4-position with R⁴; R⁴ is selectedfrom the group consisting of single-ringed aryl, single-ringedheteroaryl, C₃-C₁₄ hydrocarbyl, C₂-C₁₄ hydrocarbyloxy, phenoxy,thiophenoxy, 4-thiopyridyl, phenylazo, phenylureido, nicotinamido,isonicotinamido, picolinamido, anilino group, and benzamido; as to R²and R³: R³ is selected from the group consisting of hydrido and C₁-C₄hydrocarbyl; and R² is selected from the group consisting of hydrido,C₁-C₄ hydrocarbyl, N-piperidinyl, N-piperazinyl, N-(C₁-C₄hydrocarbyl)piperazinyl, N-pyrrolidinyl, N-morpholinyl, and —Y—Z, or R²and R³, together with the depicted carbon atom to which they are bonded,form a 6-membered heterocyclic ring, wherein each heteroatom of theheterocyclic ring is: independently selected from the group consistingof oxygen, sulfur, and nitrogen, when sulfur, optionally substitutedwith one or two oxygens, and when nitrogen, optionally substituted witha substituent, R⁵, that is selected from the group consisting ofhydrido, C₁-C₄ hydrocarbyl, C₃-C₆ cyclohydrocarbyl, C₁-C₄hydrocarbylcarbonyl, and C₁-C₄ hydrocarbylsulfonyl; —Y is selected fromthe group consisting of —O and —NR¹¹; R¹¹ is selected from the groupconsisting of hydrido and C₁-C₄ hydrocarbyl; —Z is selected from thegroup consisting of hydrido, C₁-C₄ hydrocarbyl, benzoyl,(2-pyridinyl)methyl, (3-pyridinyl)methyl, (4-pyridinyl)methyl,2-(morpholinyl)ethyl, 2-(piperidinyl)ethyl, 2-(piperazinyl)ethyl,2-(N-methylpiperazinyl)ethyl, 2-(thiomorpholinyl)ethyl,2-(thiomorpholinyl sulfone)ethyl, 2-(succinimidyl)ethyl,2-(hydantoinyl), 2-(3-methylhydantoinyl)ethyl, 2-(N-C₁-C₄hydrocarbylamino)ethyl, 2-[N,N-di(C₁-C₄ hydrocarbyl)amino]ethyl, carboxyC₁-C₄ hydrocarbyl, piperidinyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl,sulfonamide, C₁-C₄ hydrocarbylsulfonyl, C₁-C₄ hydrocarbylphosphonyl, and—C(O)—W; —W is selected from the group consisting of hydrido, C₁-C₄hydrocarbyl, C₁-C₄ hydrocarbyloxy, and —CHR¹²NH₂; and R¹² is selectedfrom the group consisting of a side chain of a D amino acid, a sidechain of an L amino acid, benzyloxy, benzylamino, and amino.
 11. Acompound or a salt thereof, wherein: the compound corresponds instructure to Formula II:

PhR⁴ is phenyl substituted at its 4-position with R⁴; R⁴ is selectedfrom the group consisting of phenyl, phenoxy, anilino, thiophenoxy,benzamido, nicotinamido, isonicotinamido, picolinamido, andphenylureido, wherein any such substituent is itself optionallysubstituted: at the meta or para position or both with a substituentthat is selected from the group consisting of halogen, C₁-C₉hydrocarbyloxy, C₁-C₁₀ hydrocarbyl, di-C₁-C₉ hydrocarbylamino, carboxylC₁-C₈ hydrocarbyl, C₁-C₄ hydrocarbyloxy carbonyl C₁-C₄ hydrocarbyl,C₁-C₄ hydrocarbyloxycarbonyl C₁-C₄ hydrocarbyl, and carboxamido C₁-C₈hydrocarbyl; at the meta- and para-positions by two methyl groups or bya C₁-C₂ alkylenedioxy group; as to R² and R³: R³ is selected from thegroup consisting of hydrido and C₁-C₄ hydrocarbyl; and R² is selectedfrom the group consisting of hydrido, C₁-C₄ hydrocarbyl, N-piperidinyl,N-piperazinyl, N-(C₁-C₄ hydrocarbyl)piperazinyl, N-pyrrolidinyl,N-morpholinyl, and —Y—Z, or R² and R³, together with the depicted carbonatom to which they are bonded, form a 6-membered heterocyclic ring,wherein each heteroatom of the heterocyclic ring is: independentlyselected from the group consisting of oxygen, sulfur, and nitrogen, whensulfur, optionally substituted with one or two oxygens, and whennitrogen, optionally substituted with a substituent, R⁵, that isselected from the group consisting of hydrido, C₁-C₄ hydrocarbyl, C₃-C₆cyclohydrocarbyl, C₁-C₄ hydrocarbylcarbonyl, and C₁-C₄hydrocarbylsulfonyl; —Y is selected from the group consisting of —O and—NR¹¹; R¹¹ is selected from the group consisting of hydrido and C₁-C₄hydrocarbyl; —Z is selected from the group consisting of hydrido, C₁-C₄hydrocarbyl, benzoyl, (2-pyridinyl)methyl, (3-pyridinyl)methyl,(4-pyridinyl)methyl, 2-(morpholinyl)ethyl, 2-(piperidinyl)ethyl,2-(piperazinyl)ethyl, 2-(N-methylpiperazinyl)ethyl,2-(thiomorpholinyl)ethyl, 2-(thiomorpholinyl sulfone)ethyl,2-(succinimidyl)ethyl, 2-(hydantoinyl), 2-(3-methylhydantoinyl)ethyl,2-(N-C₁-C₄ hydrocarbylamino)ethyl, 2-[N,N-di(C₁-C₄hydrocarbyl)amino]ethyl, carboxy C₁-C₄ hydrocarbyl, piperidinyl,2-pyridinyl, 3-pyridinyl, 4-pyridinyl, sulfonamide, C₁-C₄hydrocarbylsulfonyl, C₁-C₄ hydrocarbylphosphonyl, and —C(O)—W; —W isselected from the group consisting of hydrido, C₁-C₄ hydrocarbyl, C₁-C₄hydrocarbyloxy, and —CHR¹²NH₂; and R¹² is selected from the groupconsisting of a side chain of a D amino acid, a side chain of an L aminoacid, benzyloxy, benzylamino, and amino.
 12. The compound or saltaccording to claim 11, wherein R⁴ is unsubstituted phenoxy orthiophenoxy.
 13. The compound or salt according to claim 10, wherein thecompound corresponds in stereoconfiguration to Formula IIA:


14. The compound or salt according to claim 10, wherein: the compoundcorresponds in structure to Formula III:

X is selected from the group consisting of O, S, S(O), S(O₂), and NR⁵;R⁵is selected from the group consisting of C₁-C₄ hydrocarbyl, C₃-C₆cyclohydrocarbyl, C₁-C₄ hydrocarbylcarbonyl, and C₁-C₄hydrocarbylsulfonyl; and R⁶ and R⁷ are independently selected from thegroup consisting of hydrido and methyl.
 15. The compound or saltaccording to claim 10 wherein PhR⁴ is 4-phenoxyphenyl.
 16. The compoundor salt according to claim 15, wherein the compound corresponds instructure to Formula V:


17. The compound or salt according to claim 16, wherein the compoundcorresponds in stereoconfiguration to Formula VA:


18. The compound or salt according to claim 17, wherein the compoundcorresponds in structure to Formula VI:


19. A compound or a salt thereof, wherein: the compound corresponds instructure to Formula VII:

PhR⁴ is phenyl substituted at its 4-position with R⁴; R⁴ is selectedfrom the group consisting of single-ringed aryl, single-ringedheteroaryl, C₃-C₁₄ hydrocarbyl, C₂-C₁₄ hydrocarbyloxy, phenoxy,thiophenoxy, 4-thiopyridyl, phenylazo, phenylureido, nicotinamido,isonicotinamido, picolinamido, anilino, and benzamido; as to R² and R³:R³ is selected from the group consisting of hydrido and C₁-C₄hydrocarbyl; and R² is selected from the group consisting of hydrido,C₁-C₄ hydrocarbyl, N-piperidinyl, N-piperazinyl, N-(C₁-C₄hydrocarbyl)piperazinyl, N-pyrrolidinyl, N-morpholinyl, and —Y—Z, or R²and R³, together with the depicted carbon atom to which they are bonded,form a 6-membered heterocyclic ring, wherein each heteroatom in theheterocyclic ring is: independently selected from the group consistingof oxygen, sulfur, and nitrogen, when sulfur, optionally substitutedwith one or two oxygens, and when nitrogen, optionally substituted witha substituent, R⁵, that is selected from the group consisting ofhydrido, C₁-C₄ hydrocarbyl, C₃-C₆ cyclohydrocarbyl, C₁-C₄carbonylhydrocarbyl, and sulfonyl C₁-C₄ hydrocarbyl; —Y is selected fromthe group consisting of —O and —NR¹¹; R¹¹ is selected from the groupconsisting of hydrido and C₁-C₄ hydrocarbyl; —Z is selected from thegroup consisting of hydrido, C₁-C₄ hydrocarbyl, benzoyl,(2-pyridinyl)methyl, (3-pyridinyl)methyl, (4-pyridinyl)methyl,2-(morpholinyl)ethyl, 2-(piperidinyl)ethyl, 2-(piperazinyl)ethyl,2-(N-methylpiperazinyl)ethyl, 2-(thiomorpholinyl)ethyl,2-(thiomorpholinyl sulfone)ethyl, 2-(succinimidyl)ethyl,2-(hydantoinyl), 2-(3-methylhydantoinyl)ethyl, 2-(N-C₁-C₄hydrocarbylamino)ethyl, 2-[N,N-di(C₁-C₄ hydrocarbyl]amino)ethyl, carboxyC₁-C₄ hydrocarbyl, piperidinyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl,sulfonamido, C₁-C₄ hydrocarbylsulfonyl, C₁-C₄ hydrocarbylphosphonyl and—C(O)—W; —W is selected from the group consisting of hydrido, C₁-C₄hydrocarbyl, C₁-C₄ hydrocarbyloxy, and —CHR¹²NH₂; and R¹² is selectedfrom the group consisting of a side chain of a D amino acid, a sidechain of an L amino acid, benzyloxy, benzylamino, and amino.
 20. Acompound or a salt thereof, wherein: the compound corresponds instructure to Formula VII:

PhR⁴ is phenyl substituted at its 4-position with R⁴; R⁴ is selectedfrom the group consisting of phenyl, phenoxy, anilino, thiophenoxy,benzamido, nicotinamido, isonicotinamido, picolinamido, andphenylureido, wherein any such substituent is itself optionallysubstituted: at the meta or para position or both with a substituentthat is selected from the group consisting of halogen, C₁-C₉hydrocarbyloxy, C₁-C₁₀ hydrocarbyl, di-C₁-C₉ hydrocarbylamino, carboxylC₁-C₈ hydrocarbyl, C₁-C₄ hydrocarbyloxy carbonyl C₁-C₄ hydrocarbyl,C₁-C₄ hydrocarbyloxycarbonyl C₁-C₄ hydrocarbyl, and carboxamido C₁-C₈hydrocarbyl group, or at the meta- and para-positions by two methylgroups or by a C₁-C₂ alkylenedioxy group; as to R² and R³: R³ isselected from the group consisting of hydrido and C₁-C₄ hydrocarbyl; andR² is selected from the group consisting of hydrido, C₁-C₄ hydrocarbyl,N-piperidinyl, N-piperazinyl, N-(C₁-C₄ hydrocarbyl)piperazinyl,N-pyrrolidinyl, N-morpholinyl, and —Y—Z, or R² and R³, together with thedepicted carbon atom to which they are bonded, form a 6-memberedheterocyclic ring, wherein each heteroatom in the heterocyclic ring is:independently selected from the group consisting of oxygen, sulfur, andnitrogen, when sulfur, optionally substituted with one or two oxygens,and when nitrogen, optionally substituted with a substituent, R⁵, thatis selected from the group consisting of hydrido, C₁-C₄ hydrocarbyl,C₃-C₆ cyclohydrocarbyl, C₁-C₄ carbonylhydrocarbyl, and sulfonyl C₁-C₄hydrocarbyl; —Y is selected from the group consisting of —O and —NR¹¹;R¹¹ is selected from the group consisting of hydrido and C₁-C₄hydrocarbyl; —Z is selected from the group consisting of hydrido, C₁-C₄hydrocarbyl, benzoyl, (2-pyridinyl)methyl, (3-pyridinyl)methyl,(4-pyridinyl)methyl, 2-(morpholinyl)ethyl, 2-(piperidinyl)ethyl,2-(piperazinyl)ethyl, 2-(N-methylpiperazinyl)ethyl,2-(thiomorpholinyl)ethyl, 2-(thiomorpholinyl sulfone)ethyl,2-(succinimidyl)ethyl, 2-(hydantoinyl), 2-(3-methylhydantoinyl)ethyl,2-(N-C₁-C₄ hydrocarbylamino)ethyl, 2-[N,N-di(C₁-C₄hydrocarbyl]amino)ethyl, carboxy C₁-C₄ hydrocarbyl, piperidinyl,2-pyridinyl, 3-pyridinyl, 4-pyridinyl, sulfonamido, C₁-C₄hydrocarbylsulfonyl, C₁-C₄ hydrocarbylphosphonyl and —C(O)—W; —W isselected from the group consisting of hydrido, C₁-C₄ hydrocarbyl, C₁-C₄hydrocarbyloxy, and —CHR¹²NH₂; and R¹² is selected from the groupconsisting of a side chain of a D amino acid, a side chain of an L aminoacid, benzyloxy, benzylamino, and amino.
 21. The compound or saltaccording to claim 20, wherein R⁴ is unsubstituted phenoxy orthiophenoxy.
 22. The compound or salt according to claim 19, wherein thecompound corresponds in stereoconfiguration to Formula VIIA:


23. The compound or salt according to claim 19, wherein: the compoundcorresponds in structure to Formula VIII:

X is selected from the group consisting of O, S, S(O), S(O), and NR⁵;and R⁵ is selected from the group consisting of C₁-C₄ hydrocarbyl, C₃-C₆cyclohydrocarbyl, C₁-C₄ hydrocarbylcarbonyl, and C₁-C₄hydrocarbylsulfonyl.
 24. The compound or salt according to claim 23,wherein the compound corresponds in structure to Formula IX:


25. A compound or a salt thereof, wherein the compound corresponds instructure to the following formula:


26. A compound or a salt thereof, wherein the compound corresponds instructure to the following formula:


27. A compound or a salt thereof, wherein the compound corresponds instructure to the following formula:


28. A process for treating a host mammal having a condition associatedwith pathological matrix metalloprotease activity, wherein: the processcomprises administering a compound or a salt thereof in an MMPenzyme-inhibiting effective amount to a mammalian host having such acondition; the compound corresponds in structure to Formula I:

R¹ is a substituted 5- or 6-membered cyclohydrocarbyl, heterocyclo,aryl, or heteroaryl; the number of non-hydrogen atoms in the longestlinear chain of atoms in R¹ is greater than 6 and less than about 20atoms; R¹ defines a three-dimensional volume, when rotated about an axisdrawn through the SO₂-bonded 1-position and the 4-position of a6-membered ring or drawn through the SO₂-bonded 1-position and thecenter of the 3,4-bond of a 5-membered ring, whose widest dimension in adirection transverse to the axis of rotation is about that of onefuranyl ring to about that of two phenyl rings; as to R² and R³: R² andR³ are independently selected from the group consisting of hydrido,C₁-C₄ hydrocarbyl, heteroaryl-C₁-C₄ hydrocarbyl, aryl-C₁-C₄ hydrocarbyl,hydroxy-C₁-C₄ hydrocarbyl, C₁-C₄ hydrocarbyloxy-C₁-C₄ hydrocarbyl,aryloxy-C₁-C₄ hydrocarbyl, amino-C₁-C₄ hydrocarbyl, C₁-C₄hydrocarbylthio-C₁-C₄ hydrocarbyl, C₁-C₄ hydrocarbylsulfonyl-C₁-C₄hydrocarbyl, aminosulfonylamino-C₁-C₄ hydrocarbyl,aminocarbonylamino-C₁-C₄ hydrocarbyl, C₁-C₄hydrocarbylcarbonylamino-C₁-C₄ hydrocarbyl, aryl-C₁-C₄ hydrocarbyl,heteroaryl-C₁-C₄ hydrocarbyl, and benzyloxy-C₁-C₄ hydrocarbyl, exceptthat only one of R² and R³ may be other than hydrido or C₁-C₄hydrocarbyl, or R² and R³, together with the depicted carbon atom towhich they are bonded, form a heterocyclic ring, wherein each heteroatomin the heterocyclic ring is: independently selected from the groupconsisting of oxygen, sulfur, and nitrogen, when sulfur, optionallysubstituted with one or two oxygens, and when nitrogen, optionallysubstituted with a substituent, R⁵, that is selected from the groupconsisting of hydrido, C₁-C₄ hydrocarbyl, C₃-C₆ cyclohydrocarbyl, C₁-C₄hydrocarbylcarbonyl, and C₁-C₄ hydrocarbylsulfonyl; as to R⁶ and R⁷: R⁶and R⁷ are independently selected from the group consisting of hydrido,C₁-C₄ hydrocarbyl, heteroaryl-C₁-C₄ hydrocarbyl, aryl-C₁-C₄ hydrocarbyl,hydroxy-C₁-C₄ hydrocarbyl, C₁-C₄ hydrocarbyloxy-C₁-C₄ hydrocarbyl,aryloxy-C₁-C₄ hydrocarbyl, amino-C₁-C₄ hydrocarbyl, C₁-C₄hydrocarbylthio-C₁-C₄ hydrocarbyl, C₁-C₄ hydrocarbylsulfonyl-C₁-C₄hydrocarbyl, aminosulfonylamino-C₁-C₄ hydrocarbyl,aminocarbonylamino-C₁-C₄ hydrocarbyl, C₁-C₄hydrocarbylcarbonylamhio-C₁-C₄ hydrocarbyl, aryl-C₁-C₄ hydrocarbyl,heteroaryl-C₁-C₄ hydrocarbyl, and benzyloxy-C₁-C₄ hydrocarbyl, exceptthat only one of R⁶ and R⁷ may be other than hydrido or C₁-C₄hydrocarbyl, or R⁶ and R⁷, together with the depicted carbon atom towhich they are bonded, form a heterocyclic ring, wherein each heteroatomin the heterocyclic ring is: independently selected from the groupconsisting of oxygen, sulfur, and nitrogen, when sulfur, optionallysubstituted with one or two oxygens, and when nitrogen, optionallysubstituted with a substituent, R⁵, that is selected from the groupconsisting of hydrido, C₁-C₄ hydrocarbyl, C₃-C₆ cyclohydrocarbyl, C₁-C₄hydrocarbylcarbonyl, and C₁-C₄ hydrocarbylsulfonyl; and only one of R²,R³, R⁶, and R⁷ may be other than hydrido, C₁-C₄ hydrocarbyl, or a partof a heterocyclic ring structure.
 29. The process according to claim 28,wherein R¹ is single-ringed cyclohydrocarbyl, single-ringed heterocyclo,single-ringed aryl, single-ringed heteroaryl, wherein any suchsubstituent is: 5- or 6-membered, and substituted at its own 4-positionwhen a 6-membered ring and at its own 3- or 4-position when a 5-memberedring with R⁴; and R⁴ is selected from the group consisting ofsingle-ringed aryl, single-ringed heteroaryl, C₃-C₁₄ hydrocarbyl, C₂-C₁₄hydrocarbyloxy, phenoxy, thiophenoxy, anilino, 4-thiopyridyl, phenylazo,phenylureido, nicotinamido, isonicotinamido, picolinamido, andbenzamido.
 30. The process according to claim 28, wherein: R¹ is phenylsubstituted with R⁴ at the 4-position; and R⁴ is selected from the groupconsisting of phenyl, phenoxy, anilino, thiophenoxy, phenylazo,benzamido, nicotinamido, isonicotinamido, picolinamido, andphenylureido.
 31. The process according to claim 28, wherein: R¹ isphenyl substituted with R⁴ at the 4-position, and R⁴ is phenyl, phenoxy,anilino, thiophenoxy, phenylazo, benzamido, nicotinamido,isonicotinamido, picolinamido, and phenylureido, wherein any suchsubstituent is substituted: at the meta- or para-position or both with asubstituent that is selected from the group consisting of halogen, C₁-C₉hydrocarbyloxy, C₁-C₁₀ hydrocarbyl, di-C₁-C₉ hydrocarbylamino, carboxylC₁-C₈ hydrocarbyl, C₁-C₄ hydrocarbyloxy carbonyl C₁-C₄ hydrocarbyl,C₁-C₄ hydrocarbyloxycarbonyl C₁-C₄ hydrocarbyl, and carboxamido C₁-C₈hydrocarbyl, or at the meta- and para-positions by two methyl groups orby a methylenedioxy group.
 32. The process according to claim 28,wherein the number of non-hydrogen atoms in the longest linear chain ofatoms in R¹ is greater than 8 and less than 18 atoms.
 33. The processaccording to claim 30, wherein R⁴ is unsubstituted phenoxy orthiophenoxy.
 34. The process according to claim 28, wherein saidcompound or salt is administered a plurality of times.
 35. The compoundor salt according to claim 18, wherein the compound corresponds instructure to the following formula:


36. The compound or salt according to claim 21, wherein the compoundcorresponds in structure to the following formula:


37. The compound or salt according to claim 21, wherein the compoundcorresponds in structure to the following formula:


38. The compound or salt according to claim 21, wherein the compoundcorresponds in structure to the following formula:


39. The compound or salt according to claim 18, wherein the compoundcorresponds in structure to the following formula:


40. The compound or salt according to claim 18, wherein the compoundcorresponds in structure to the following formula:


41. The compound or salt according to claim 18, wherein the compoundcorresponds in structure to the following formula:


42. The compound or salt according to claim 18, wherein the compoundcorresponds in structure to the following formula:


43. A compound or a salt thereof, wherein the compound corresponds instructure to the following formula:


44. A compound or a salt thereof, wherein the compound corresponds instructure to the following formula:


45. The compound or salt according to claim 21, wherein the compoundcorresponds in structure to the following formula:


46. A compound or a salt thereof, wherein the compound corresponds instructure to the following formula:


47. The compound or salt according to claim 24, wherein the compoundcorresponds in structure to the following formula: